极T放射磁共振全球科研集锦

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极T放射磁共振全球科研集锦

极T代谢磁共振全球科研集锦 4 目 录序言..........................................................................................................................1极T代谢磁共振介绍 ............................................................................................6代谢组学................................................................................................................................... 7超极化代谢磁共振技术 ............................................................................................................ [收起]
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极T放射磁共振全球科研集锦
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极T代谢磁共振全球科研集锦

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目 录

序言..........................................................................................................................1

极T代谢磁共振介绍 ............................................................................................6

代谢组学................................................................................................................................... 7

超极化代谢磁共振技术 ......................................................................................................... 7

全球超极化研究热点 ...................................................................................................... 8

全球重点科研文章集锦 ................................................................................................. 9

综述篇 .....................................................................................................................................11

ג极ࣅ磁共振հ೷研৯৊ቛ............................................................................................................................................................. 12

Biomedical Applications of the Dynamic Nuclear Polarization and Parahydrogen Induced Polarization Techniques for Hyperpolarized 13C MR Imaging....................................................................................................................................22

Hyperpolarized 13C MRI: State of the Art and Future Directions ..........................................................................................40

肿瘤篇 .....................................................................................................................................55

Development of Methods and Feasibility of Using Hyperpolarized Carbon-13 Imaging Data for Evaluating

Brain Metabolism in Patient Studies................................................................................................................................................56

Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-13C] Pyruvate ................................68

Hyperpolarized 1-[13C]-Pyruvate Magnetic Resonance Imaging Detects an Early Metabolic Response to Androgen Ablation Therapy in Prostate Cancer...............................................................................................................................80

Investigation of analysis methods for hyperpolarized 13C-pyruvate metabolic MRI in prostate

cancer patients.......................................................................................................................................................................................... 84

Characterization of serial hyperpolarized 13C metabolic imaging in patients with glioma ................................... 103

Hyperpolarized 13C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone

and liver: a clinical feasibility study................................................................................................................................................ 115

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极T代谢磁共振全球科研集锦

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心血管篇 .............................................................................................................................. 127

Hyperpolarized 13C Metabolic MRI of the Human Heart: Initial Experience ................................................................. 128

Efect of Doxorubicin on Myocardial Bicarbonate Production from Pyruvate Dehydrogenase in Women with

Breast Cancer ...............................................................................................................................................................................................................................144

Noninvasive In Vivo Assessment of Cardiac Metabolism in the Healthy and Diabetic Human Heart Using

Hyperpolarized 13C MRI ........................................................................................................................................................................150

Proof-of-Principle Demonstration of Direct Metabolic Imaging Following Myocardial Infarction Using Hyperpolarized 13C CMR .................................................................................................................................................................................. 164

神经篇 .................................................................................................................................. 171

First Hyperpolarized [2-13C] Pyruvate MR Studies of Human Brain Metabolism ....................................................... 172

Kinetic Modeling of Hyperpolarized Carbon-13 Pyruvate Metabolism in the Human Brain ................................ 194

Lactate topography of the human brain using hyperpolarized 13C-MRI ........................................................................ 204

Quantifying normal human brain metabolism using hyperpolarized [1-13C]pyruvate and magnetic

resonance imaging ....................................................................................................................................................................................................................221

Imaging acute metabolic changes in mild traumatic brain injury patients using hyperpolarized [1-13C]pyruvate .......232

技术篇 .................................................................................................................................. 247

Spatio-Temporally Constrained Reconstruction for Hyperpolarized Carbon-13 MRI Using Kinetic Models ..................248

Hyperpolarized 13C MRI data acquisition and analysis in prostate and brain at University of California,

San Francisco ................................................................................................................................................................................................................................260

Translation of Carbon-13 EPI for hyperpolarized MR molecular imaging of prostate and brain

cancer patients........................................................................................................................................................................................278

Technique development of 3D dynamic CS-EPSI for hyperpolarized 13C pyruvate MR molecular imaging of human

prostate cancer ...........................................................................................................................................................................................................................288

写在最后............................................................................................................ 310

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ٗ 1895 ౎୿ൗ݀၄ X พ၍ᅜઠLjঢ়ࡗକॽৎ 130 ౎ڦ݀ቛLjᆖၟბڦ৊օ代՗ጣᅅბ

ਆă߭ڦ܏ᅅბኑࢅၟՎକᅅბᆖ߀ڹןօLj৊ڦ

ٗ X พ၍ڟ CTĂ磁共振ĂPET-CTĂPET-MRI ڪබׯࢇ๮ၟ܎Ljٗ࿿૙ׯၟڟຕጴׯၟLj

ၟđLjᆖၟׯీࠀĐڦ၄ሞڟ೪၂๖đ঴ĐڦكڇٗLjၟׯጱݴࢅၟׯ࠵ྲڟၟׯႚༀბٗ

ႜᄽ৊෇କᅃ߲׉ݥ࿀ڦۇٴ้代ă

ᆖၟ݀ቛٗ࿿૙ׯ෇৊ၟຕጴׯၟۇٴ้代LjยԢ৊օ๟࠲॰ǗยԢڦ۞代߸ႎᅜत೵त

ᆌᆩॽᆖၟኑଐླྀ෇କ৛ጚ้代ăٗरຍݛ௬ઠੂLjۇٴຕ਍Ăሊऺ໙ĂፇბĂට߾ీ዇Ă࿿

૴ྪĂ൶੷૾ڪरຍLjܔۼᆖၟბڦ݀ቛׂิକփཞྼ܈Ăփཞ֫௬Ăփཞڦ܈ײླྀۯLjླྀ

ۯᆖၟბ科৊෇କᅃ߲݀ቛڦ੺ڢכă

ยԢᇑरຍڦ݀ቛظႎLj૗փਸᆖၟ׍ฆڦኧ׼ăߌ谢 GE ࠅິፕྺᆖၟยԢڦዷᄲิ

ׂ׍ฆLjీࠕᅃ኱ዂ૰ᇀྺዐࡔ༵ڦ܋ߛࠃยԢࢅႎڦरຍǗߌ谢 GE ࠅీິࠕׂิ研݀߸

ڦܠཱིԨࣅ೗ׂඟዐࡔᆩࢽሞڼᅃ้क़๑ᆩႎڦरຍࢅႎڦยԢೝ໼ă

ג极ࣅ磁共振代谢ׯၟरຍLj๟ GE ࠅິ磁共振ገࣅᅅბೝ໼ڦፇׯኮᅃLj໲੗ᅜํ၄

磁共振႑ڦࡽๆྤԠ༵ืăణമLjᆖၟरຍᅙঢ়ླྀڟۯକ代谢ᆖၟڦႎ้代ăᇑُཞ้Lj代

谢ᆖၟీܔࠕᇀ৛ጚೠࠚĂ৛ጚዎଐྺࢃ႐ڦᆖၟኸڞᇱሶ༵ࠃକ߸৛ጚڦԍቱă全球ܔᇀ

޿रຍڦ科ბ研৯ᅙঢ়ᆶକᅃۨࡕׯڦLj科研࿔၅ణമᅙٳ 2000 ᇆೊăኄԨ科研集锦৛჋

କഄዐڦᅃևݴ৛ࣀ࿔ቤLjཚࡗ࿔ቤڦბသࢅ૙๹Lj࿢்੗ᅜڦࡻ࢔କ঴ࢅණ๎ڟኄᅃरຍ

ቛă৊ፌႎڦ໼ೝࢅ

ᅜ࣒ኁྺዐ႐Ljႎ႗रຍྺሜ༹Ljፌۇٴ၌ڦ܈ࣩ݀ᆖၟሞĐॳ੃ዐࡔđዐڦፕᆩă࿢்

ᆌᆩăࢅں஌ڦႎरຍۯླྀፕᆩLjᅃഐۇٴፌഄࣩ݀ࠕీLjॆ׍ၟᆖ߳ڦᅃᄣິࠅ GE ཞځ೺ᄺ

刘士远

ዐࣀᅅბݣࣷพბࣷݴዷඪ྿ᇵ

ฉ׊࡛ኙᅅᇾ

Ⴞ ჾ

1

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Ⴞ ჾ

磁共振ׯ) ၟMRI) ๟ 20 ๘ु 80 ౎代؛ླྀࣄڦ؜้代ڦᅅბᆖၟბॠֱरຍLjഄ集࿿૙Ă

ࣅბĂຕბĂऺ໙ऐბĂิ࿿ბࢅᅅბڪᇀᅃ༹Ljਏᆶഄ໱ᆖၟბॠֱरຍ࿮੗Բెڦᆫ๞Lj

Lj研ڪ૰ీڦၟׯጱݴᅜत࡞໦พޖ࿮Ljీ૰ڦ֫ൎ࿋ඪᅪݛܠLj܈Բܔፇኯ෉ڦԲසᆫᅴ

৯ࡕׯ֫؜փ൬ , ଣضᆌᆩݔྷփ܏ྊቛă

磁共振ג极ࣅरຍ੗ᅜ๑ᇱጱڦࢃ႑ࡽ ื༵1-10 ྤԠLjܸٗ๑ᇱઠవᇀׂิ႑ࡽई极

༵ଶᇘLjڦၟׯጱݴྊቛ磁共振ۇٴۇٴLjॽၟׯᆩᇀࡽডഽ႑ׂิࢃᇱጱڦࡽ႑ၟׯෑ磁共振

ߛኑ܏ڦ௺ߌႠࢅ༬ᅴႠă੗ᅜຫLj磁共振ג极ࣅरຍਸྊକ MRI ڦᆼᅃ߲ႎଶᇘLj࿢ศ႑Lj

ሞג极ࣅरຍڦ݀ቛࢅኧ׼ူLj磁共振࿄ઠڦ科ბ研৯ᆼॽ৊෇ᅃ߲ႎ঩܎Lj磁共振ڦଣض

ᆌᆩᄺॽ৊෇ᅃ߲ႎחߛă

ራሞब౎മLj࿢்ሼࢅӎࢲຯۇٴბڦᆖၟዐ႐৊ႜࢇፕLjሞࡔ՗݀ాକڼᅃೊ࠲ᇀג极

ࣅ C13 ڦዐ࿔ጹຎLjٗఫ้ഐ࿢்৽޿ܔरຍ؊஢କ೺ځăړ඗Lj׉ݥඵ႞Ԩກᄺ๭୤କ

޿ೊ࿔ቤăডྺᅍڦ࡮๟LjᆯᇀዖዖᇱᅺLj࿢்࿄ీኈኟڦᆛᆶࢅํ၄ኄᅃरຍժ৊ႜ研৯ă

ཞ้ዐࡔࡔాᄺሡ้ுᆶጎऐăኄԨᆶ࠲磁共振ג极ࣅरຍڦ科研集锦Lj๭୤କ࠲ᇀג极ࣅ

代谢磁共振ڦᅃևݴঢ়ۆ࿔၅Ljྺۇٴॆକ঴磁共振ג极ࣅरຍࡔाࢅፌႎമᄂरຍ༵ࠃକᅃ

߲شڦࡻ࢔੨ăሞኄ૛Lj࿢ᄺ代՗߳࿋܁ኁߌ谢 GE 磁共振ׂ೗ևྺኄԨ磁共振ג极ࣅरຍ

科研集锦؜ڦӲ໯ፔڦ౮૰ă࿢ᄺထྭLjኣዝۇٴბڼᅃ޹ຌᅅᇾీࠕ੺৑ᆅ৊ኄၜरຍLj࿄

ઠ੗ᅜࢅ全ࡔయ዁全球ڦጆॆᅃഐሞኄᅃፌമᄂڦरຍଶᇘ৊ႜ঍ୁࢇፕă೺ځ磁共振ג极

ࣅरຍփ܏ظႎᅜत科研ᇑଣض共ཞ੺໏ླྀ৊Ljཞ้Ljླྀۯ磁共振ג极ࣅरຍሞዐڦࡔ஌ںLj

ኁă࣒ڦܠ߸ޟLjሰضଣ৊෇ں੺৑Ljࡕׯڦܠ߸؜ׂ

程敬亮

ዐࡔ研৯႙ᅅᇾბࣷ磁共振ጆᄽ྿ᇵࣷዷඪ྿ᇵ

ኣዝۇٴბڼᅃ޹ຌᅅᇾޭᇾ׊

2

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磁共振रຍሞݧ݀໏ቛ , ፕྺ৛ጚኑଐڦዘᄲ૰ଉ , ሞĐๆ຺࿵đࣄࡀਸೊኮा , ܋ߛ

ᅅଐยԢڦ݀ቛॽᆓઠႎ܈ߛڦă磁共振ᆖၟยԢణമ੺໏݀ቛLjփৈਏᆶ෉ፇኯܔԲߛ܈Lj

࿮ظ࿮ޖพڪᆫ๞Ljܔᇀᅃၵदթڦኑ܏ࢅෲֱਏᆶๆݴዘᄲڦᅪᅭăٗएإଣڟضገࣅᅅ

ბምڟ৛ጚᅅბLj磁共振ᆖၟरຍۼࣩ݀କ਎ڦۇٴፕᆩă

גपࣅ代谢ׯၟ磁共振Lj๟ገࣅᅅბଶᇘڦዘԁ૧ഗኮᅃăཚגࡗ极ࣅरຍLj੗ᅜॽ磁

共振႑ࡽ૙ஃ༵ื 10 ྤԠLjᇺגሁ 7T ฯ዁ 10T ߛגׇ磁共振ڦ႑ࡽื༵Lj๑ڥ磁共振ᅺ

ُ੗ᅜڟٳኈኟݴጱᆖၟڦೝ຤LjܸٗྜׯକᆖၟยԢٗ代谢ݴڟጱࠀڟీڟ঳ڦࠓገࣅᅅ

ბ全ୁڦײޮ߃ăᅅბ代谢ፇბڦბ科݀ቛৎ౎ઠᄺᅃ኱ྷජᅅბڦ݀ቛփ܏മ৊Ljٗဣཥ

ิ࿿ბڟገࣅᅅბLjምڟ৛ጚᅅბă磁共振ᆖၟ࿄ઠॽጽၠթ૙ᆖၟํ้代谢ڦႎ้代ă

ࡗג科研࿔ቤᅙࣅ极גڦाฉࡔक़Lj้ڦ౎ቛᅙᆶๆᇆ݀磁共振रຍሞ全球ࣅ极ג

2000 ᇆೊLj研৯ࡕׯๆݴဠටLjܔᇀമଚ၇ҵ࣏ᆶ୕ా዗ୀᅙᆶডྺׯຄڦ科研৊ቛLjሞ

หঢ়ဣཥदթڦ科研༑໭ᄺሞደօׯຄLjਐ૗ଣضኻᆶᅃօኮᄫăڍ๟ణമሞࡔా࣏ுᆶጎ

ऐLj၎႑ࡔܠ࢔ాڦཞඦࢅ࿢ᅃᄣLjထྭኄᄣڦरຍ৑੺ሞዐࡔ஌ںLjඟ࿢்代谢ፇბࢅ৛

ጚᅅბᄺ߶ฉࡔाڦগօă

ፌࢫLjଣڦض݀ቛ૗փਸ科研ڦኧ׼Lj科研ڦ݀ቛᄺཞᄣ๟एᇀࢅ஢ፁଣضႴ൱ă磁共

振ᆖၟरຍڥᅜݧ݀໏ቛ૗փਸ߳࿋ཞඦڦ共ཞ౮૰ă࣮๯ࡗඁLjዐڦࡔ磁共振๚ᄽڥᅜტ

໏݀ቛLj૗փਸႎरຍڦᆅ৊ࢅଣضฉڦփ܏۞代Ljᄺ࣌ᆓሁઠሁܠኄᄣڦ࿔၅ࣹጺᇑ঍ୁă

宋 彬

ዐࣀᅅბݣࣷพბࣷݴޭዷඪ྿ᇵ

ဇᅅᇾࣀბۇٴج຺

Ⴞ ჾ

3

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Ⴞ ჾ Preamble

GE ᅅଐ๟全球ᅅଐरຍࠅິLj科रظႎ๟ GE ᇑิਓઠڦ DNAă1973 ౎ GE ײ߾฾ᅉ

ྑܻ ॊүޡᅺྺ研݀؜සࢆ๑ۉጱحሁਨᇹ֌ଙLjइڥ౷Ԟܻ࿿૙ბঃLjᄺᅺྺኄ߲研৯

ࡕׯLj๘হڐิକڼᅃ໼全ว磁共振 MRIă1983 ౎LjGE ټઠକ๘হฉڼᅃ໼ᅅᆩ 1. 5T ڞג

磁共振ăGE ᅃ኱ዂ૰ᇀ঴ਦᅅბଶᇘڦవ༶Ljགցႜᄽरຍ੣ӣăසৃ࿢்ڦ极 T 代谢磁

共振Ljਸഔକํ้代谢ᆖၟڦႎ้代Ljॽ磁共振ׯ෇ླྀၟᅃ߲ႎڦᛥރ้代ă

极 T 代谢磁共振ཚגࡗ极ݛڦࣅ๕Lj੗ᅜ৊ႜऄ༹ํ้代谢ׯၟLjॽ磁共振႑ࡽื༵

10 ྤԠLjגڟٳሁ 7T ฯ዁ 10T ڦ႑ࡽၳࡕă极 T 代谢磁共振ኮఁᄺᆯُܸઠă

极 T 代谢磁共振๟ GE 磁共振ܠ౎ڦ科研ࣹጺत৛ࣀLjణമᅙঢ়ሞ全球 26 ॆۥपᅅଐ

ऐࠓጎऐ๑ᆩժਸቛ科ბ研৯Ljᆩࢽጲ݀ႚׯକ全球ג极ׯࣅၟڦ科研ංLjۨ೺ਉӸბຍऄ

ۯăᇑ GE ڦ科研ཷܓ৊೺ۨႜ঍ୁݒࢅઍă

ࡗג࿔ቤ݀՗ଇӥೊLjణമ共ࡗג࿔ቤڦ՗݀౎௅Ljۅቛඤ݀ڦႜᄽၟ๟ׯ 13C ࣅ极ג

2000 ೊLjഄዐԈઔ NatureĂScience ۥڪप೺਽ݴߛڦ࿔ቤăᆯᇀೊޗᆶ၌LjኄԨ科研集锦

ৈ๭భକ 22 ೊ࿔ቤLjᇑۇٴॆݴၛ全球ሞג极ࣅଶᇘڦ科研ඤۅăኍܔփཞڦᆌᆩݛ்࿢ၠ

৊ႜକ๹૙Ljཞ้௅ᅃೊ࿔ቤ࿢்ۼ৛႐ጚԢକ࿔၅܁ڞLjසᆶփፁኮتLj൩߳࿋ጆॆ಼ೠ

ኸኟă

GE ᅃ኱զ׶ጣᅜरຍ૬วLjᅜޜခ૬႐Ljᅜࢇፕ૬ԨڦᇱሶLjփ܏༑໭മᄂरຍଶᇘLj

཭೦ظႎăထྭ GE 磁共振ీࠕᇑ߳࿋ጆॆᅃഐླྀ৊रຍظႎतଣض科研ڦ݀ቛLj谢谢ƽ

赵霞

GE ᅅଐ ( ዐࡔ ( 磁共振ׂ೗๚ᄽևጺঢ়૙

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极T代谢磁共振介绍

磁共振ᆖၟ݀ቛ዁ৃLjዷᄲڦᆌᆩධ৹ཕାሞدཥڦ঳ࠓĂࠀ֫ీ௬ă代谢ፇბ๟ीएᅺፇბĂገ୤ፇბĂڒ

ӣዊፇბLjፌႎ݀ቛഐઠڦፇბ研৯ඤۅLj੗ᅜۯༀڦ௮ຎට༹ڦ代谢ᅴ׉Ljժీࠕ໏੺Ljጚඓڦೠࠚदթڦጒༀ

ᄇՎăࢅ

GE ዂ૰ᇀظႎरຍڦ研݀Ljླྀ؜କ极 T 代谢磁共振ဣཥLj੗ᅜํ၄ܔऄ༹代谢ڦײࡗ้ํׯၟă极 T 代谢磁共

振ᆯଇևݴፇׯLjᅃ߲๟极ࣅᅏ SPINlabLjᅃ߲๟ׯ ໼ೝၟPremier ࢃܠ໼ೝă

磁共振ᅃӯۼ৊๟ႜൠᇱጱׯၟLjዷᄲڦᇱᅺ๟ᆯᇀ࿢்ට༹ా 70% ᅜฉۼ຤๟Ljܸ൐ൠᇱጱԨวڦጲ඗܈ݿ

ࢅ磁共振႑ࡽ௺ۼ܈ߌ๟ፌڦࡻăᅺྺ႑ࡽྲෑLj࿢்ሞࡀ׉ଣض 3.0T तᅜူڦ磁共振ฉLjۼփࣷ৊ႜഄ໱ࢃ໎ڦ

෢௮ăܸཚࡗ்࿢ڦ极ࣅᅏ SpinlabLj৊ႜڹ࿿ג极ࢫࣅLj੗ᅜӝ磁共振႑ࡽ ื༵10 ྤԠLjגڟٳሁ 7T ฯ዁ 10T ڦ

႑ࡽၳࡕă极 T 代谢磁共振ኮఁᄺᆯُܸઠă

ሞ代谢磁共振༑ኍݛ௬࿢்჋ስ C13Ljኄ૛ᆶब߲ᇱᅺLj๯ံ C ๟ᆶऐݴጱڦࠡॐڦዘᄲׯࠓLjܸ൐ݴܔጱ঳

ڦࠓՎڦࣅ௺܈ߌ๟ൠᇱጱڦ 10 ԠLjُྔ C13 ๟ݣݥพ࿿ዊLjܔට༹׉ݥҾ全LjփټࣷઠඪݣڦࢆพႠ໦ฅăܸ

ܔᇀׯ࿿ၟዊ࿢்჋ስڦ ๟C13 Քऻڦեཛྷ໗Ljኄ๟ᅺྺեཛྷ໗تᇀට༹ీଉ代谢ڦᅃ߲࠲׉ݥ॰ڦ࿋ዃăሞኟ׉

ڦ൧઄ူLjեཛྷ໗ঢ়ࡗෙ᷌໗თ࣍ิׯ ATPLjܸሞ݄ᄟڦ൧઄ူሶิׯළ໗ăܸܔᇀ዗ୀፇኯLjनՍሞݥ݄ᄟڦ൧

઄ူLjᄺࣷᆶۇٴଉڦեཛྷ໗ገׯࣅළ໗LjߴࠃҵဦԇLjኻᆶ࢔ณڦᅃևݴեཛྷ໗ࣷीჄิׯ ATPă࿢்৽๟૧ᆩኄ

߲ᇱ૙Ljཚࡗ磁共振ׯၟLj࠵ִጀพڟా༹ঢ়גࡗ极ڦࣅ C13 Քऻڦեཛྷ໗ሞ዗ୀև࿋ገׯࣅළ໗ײࡗڦLjํ้࠵

֪዗ୀဦԇڦ代谢ՎࣅLjཞ้੗ᅜཚࡗ代谢໏୲৊ႜۨଉݴဆăܔᇀदթઠ঄Lj代谢ڦՎࣅံ๟ྫྫᇀဦԇፇኯڦ

ႚༀՎڦࣅLjᄺ৽๟ຫ代谢ॠ֪Բ࿢்دཥڦॠ֪ݛ๕߸ራ೺Ă߸௺ߌăC13 Քऻڦեཛྷ໗ ( ణമኟሞ FDA ܾ೺ଣض(

أକ৊ႜ዗ୀݛၠڦ研৯Ljཞ้ᄺሞ႐ሤĂߊሤĂะሤĂᅐ၇Ăළ၇ĂᄁኢDŽԈઔᄁኢޅԓDžݛڪ௬ۼᆶփณ研৯ă

ཞᄣ C13 Քऻڦեཛྷ໗ኻ๟代谢༑ኍڦᅃዖLjփཞڦ代谢༑ኍਏԢփཞڦ代谢༬ᅴႠLj၄ሞᄽాᅙঢ়ᆶबๆዖ代谢

༑ኍሞ߲߳ݛ௬৊ႜጣට༹代谢ڦ研৯ă

ణമ GE ᅙঢ়ࢅ Stanford ࢅ UCSF ଇॆࡔाۥपᅅბᇾڦገࣅᅅბዐ႐৊ႜକศࢇڦ܈ፕLjժྺኄଇ߲ገࣅᅅბ

ዐ႐༵ࠃକ GE ڦĐ15Tđڦ঴ਦݛӄDŽSIGNA 7T ࢅ极 TDžሞᇑኄଇ߲全球ۥपገࣅᅅბዐ႐ࢇڦፕዐLjGE ᄺओેକ

ፕᇑॺยঢ়ᄓăࢇڦᅅბዐ႐ࣅገڦଉۇٴ

৽研৯ၜణઠੂLjGE ᇑ Stanford ࢅ UCSF ڦ科研ࢇፕLjภतڟեཛྷ໗ڦ༑ኍሞ዗ୀᅜत߲߳ሤഗڦᆌᆩLjႎڦ

C13 Քऻ代谢༑ኍڦ研݀Ljᅜतեཛྷ໗༑ኍሞଣضኑ܏ฉ؛ڦօํ७LjԈઔܔᇀമଚ၇ҵڦራ೺ኑ܏Ă዗ୀݴपĂ

ᅜतଐၳೠڪࠚ߲߳ᇑ৛ጚᅅଐ৆௢၎ڦ࠲ాඹă

أඁᇑኄଇॆገࣅᅅბዐ႐ࢇڦፕLj极 T 代谢磁共振࣏஌ڟࢽ全球 24 ॆഄ໱ۥڦपڦ科研ऐࠓLjժႚׯକ࿢

்ڦ极ׯࣅၟڦ科研ංጱLj׬ኮྺ Research Circle TechnologyLj࿢்ࣷᆶۨ೺ڦბຍऄۯLjᄺᆶ NIH ኸۨڦಢჟዐ႐ă

࿮ᅑ C13 ג极ׯࣅ๟ၟႜᄽڦ݀ቛඤۅLj௅౎݀՗ڦ࿔ቤࡗגଇӥೊLj၄ሞጺ共݀՗࿔ቤᅙঢ়ࡗ 2000 ೊLjഄ

ዐփ݄Ԉઔ NatureĂScience ۥڪप೺਽ݴߛڦ࿔ቤă

极 T 代谢磁共振ӝ࿢்၄ሞፌമᄂڦ代谢ፇბ研৯ᇑణമፌံ৊ڦ磁共振ׯၟरຍ঳ࢇഐઠLjඁ༑൱ܔॳ்࿢

੃ิऄፌዘᄲڦ዗ୀLj႐సदթڪዘۇٴदթڦ৛ጚᅅଐڦ঴ਦݛӄ , 极 T 代谢磁共振ᅃۨీࠕٗ科研ጽၠଣضLjժ

ፕᆩăڦओ极߸Ăۇٴ߸ࣩ݀

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ሞଣض໯ሞڦට༹༹࿒तׇഽူLj磁共振ڦ႑ሯԲᆯᇀ๴၌ᇀጲ඗ࢃگࢅ܈ݿጲ჉极ࣅ୲LjԲഄ໱ׯၟݛ๕گă

ܸ 13C ڦ჉磁Բሀྺ 1H ڦ຺ݴኮᅃLj໯ᅜ 13C ᇑ 1H ڦ၎ܔ႑ࡽԲྺ 0.016Ljेኮ 13C ڦጲ඗گ܈ݿDŽ13C ৈ቞ሀ 1.1%Dž

ܸ 1H ڦጲ඗܈ݿ ྺ99%Lj႑ࡽֶਐ৊ᅃօઙۇٴăྺକ߀ ฀13C ڦ MRI ႑ࡽLj੗ᅜට߾ื༵ݴጱዐ 13C Քऻڦ౪܈Lj

ᅃӯ੗ᅜ༵ื዁ 99%ăُྔLjMRI ႑࣏ࡽ੗ᅜཚגࡗ极ݛڦࣅ݆၂ዸ༵ߛ 10 ྤԠLjܸፌ׉ᆩגڦ极ࣅྺ݆ම঴๕

ۯༀࢃ极ࣅ) ݆dissolution-Dynamic Nuclear Polarization)DŽၘ९޹୤ᅃDžă

磁共振ג极ࣅ代谢ׯၟፌߌ႗඀ڦ ๟13C ᇮ໎Ljᅺྺ༐๟ิంዐፌएԨڦิࣅᇮ໎ኮᅃLjܸ൐ 13C ๟࿘ۨཞ࿋໎Lj

࿮ޖพLj൐ਏᆶডڦߛ磁Ⴀऄሂ܈ă13C ݴܔጱ঳ࠓՎڦࣅ௺܈ߌԲ 1H ۇٴ 10 ԠLjܸᅃӯ൧઄ူLj代谢਩ࣷᆅഐݴ

ጱ঳ࠓฉڦՎࣅăُྔLjג极ࣅ 13C रຍڦଷᅃ߲ᆫۅ੗๟ᅜ极ڦࣅ༑ኍዖૌܠ׉ݥLjۇٴଉࡤ޷ڦ 13C ڦాᇸႠิ࿿

ݴጱDŽ代谢ڹ࿿Džᅙঢ়ԥ研዆؜ઠժᆩᇀ研৯ܠዖ዗ୀLjᄁኢࢅ代谢Ⴀदթ၎ڦ࠲代谢ࢅ૙ิײࡗLjසူ՗໯๖ă

ങৃྺኹLj研৯ፌגڦݘ࠽极ࣅ༑ኍ๟ [1-13C] եཛྷ໗ă໲极ࣅႠࡻDŽሞଣضᆩ๑ᆩཉॲူፌߛ੗ٳ 50%DžLjժ

൐ਏᆶডڦ׊ T1DŽ3.0 T ้ሞමᅂዐሀ 67 ௱DžLjᅺُ႑ሯԲፁߛࠕ੗ᅜ৊ႜ༹ా研৯ăዘᄲڦ๟Lj[1-13C] եཛྷ໗๟

܈ߛ࿿ิბ၎ڦ࠲༑ኍLjᅺྺեཛྷ໗࿋ᇀܠዖ代谢཰০࠲ڦ॰ݴኧۅLjԈઔ༛ট঴Ljෙ᷌໗DŽTCADžთࢅ࣍ҽए໗

ׯࢇăጀ෇ิంဣཥࢫLjג极ࣅ] 1-13C] եཛྷ໗ტ໏ဌ๭ڟဦ

ԇዐLjժཚࡗළ໗ྃൠாDŽLDHDžࢅեҽ໗ገҽாሞဦԇዊ

ዐ代谢ྺ [1-13C] ළ໗ࢅ] 1-13C] եҽ໗ăג极ࣅ] 1-13C] եཛྷ໗

ᄺԥገሏڟ၍૭༹ዐLjժԥեཛྷ໗ྃൠாDŽPDHDžገࣅ ྺ13C

CO2ࢅᅚḅޤாALjܸٗፕྺPDHऄႠ՗ኙࢅTCAთڦ࣍ཚଉă

[1-13C] եཛྷ໗၄ሞᅙݘ࠽ᆩᇀଣضമڦ߳ዖदթఇ႙DŽ૩ස

ҵኢLjਆևඍეࢅᄁኢDžዐڦ代

谢研৯ăܸ൐Lj໲࣏ሼᆅ෇ڟଣ

ض代谢研৯Ljժԥኤ௽๟Ҿ全੗

ႜڦăణമLj[1-13C] եཛྷ໗ᅙঢ়

ฤ൩ঢ়ฤ൩ FDA ණኤLjኟتሞଣ

ăܾ೺ض

代谢组学(Metabolomics)

超极化磁共振成像 (Hyperpolarization NMR)

代谢ፇბ๟ 20 ๘ु 90 ౎代఍ႎ႙ڦᅃோბ科Lj๟ीएᅺፇბĂ

ڒӣዊፇბࢅገ୤ፇბኮڦࢫႎ႙ፇბLj๟ဣཥิ࿿ბڦዘᄲፇׯև

ݴLjᅙঢ়ݘ࠽ᆌᆩᇀิ࿿ĂᅅᄱĂྲิ࿿त࣍ৣଶᇘăएᅺፇბڒࢅ

ӣዊፇბݴ՚ٗएᅺڒࢅӣዊ֫௬༑ლิంڦӎ௞Ljܸဦԇాܠ࢔Վ

ڪĂဦԇक़ཚ႑ڿدଉీĂݣ๥ࡽLjසဦԇ႑ڦ௬֫ሞ代谢๟݀ิࣅ

ۼ๴๟代谢ۙ੦ڦăሞᅅბଶᇘLj代谢ፇბጣዘ研৯ิ࿿༹Ăഗ࠳ĂፇኯईဦԇዐాᇸႠ代谢࿿๴ాሞईྔሞᅺ໎

ᆖၚڦՎࡀࣅୱăएᅺᇑڒӣዊڦ՗ٳ௢৆၎࠲Ljܸ代谢࿿ሶ߸ݒڦܠᆙକဦԇ໯࣍ڦتৣLjኄᆼᇑဦԇڦᆐᄢጒༀĂ

ᄱ࿿࣍ࢅ࿫ৣක࿿ڦፕᆩतഄ໱ྔহᅺ໎ڦᆖၚ௢ൎ၎࠲ăएᅺፇბڒࢅӣዊፇბߢ໕ే๊஺੗ీ݀ิLjܸ代谢ፇ

ბሶߢ໕ే๊஺ඓํ݀ิକă

代谢ፇბሞႎᄱڦҾ全ႠೠࠚĂ۾૙ბĂิ૙ბĂዘۇٴदթڦራ೺ኑ܏Ă߲ႠࣅዎଐĂࠀీएᅺፇბĂዐᄱ၄

代ࣅĂ࣍ৣೠࠚĂᆐᄢბࢅ໱ഄ科ბଶᇘዐਏᆶ极ഄݘ࠽ܸዘᄲڦᆌᆩă代谢ፇბช࿮݆全௬৊෇৛ጚᅅბࢅ၎࠲

ॳ੃ଶᇘ༵ࠃׂᄽޜࣅခLjዷᄲ೟ৡᆶଇ߲ǖᅃ߲๟Քጚࣅ࿚༶Ljܾ๟ཚଉڦ࿚༶ă代谢ፇბၠമ݀ቛڦᅃ߲Ղঢ়

ኮୟ৽๟ۨଉࣅᇑՔጚࣅă

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全球超极化研究热点

ణമLjሞ全球ᆶ 26 ॆۥॖۇٴბत研৯ऐࠓሞਸቛ

ბĂຯ།ۇٴൃॵბĂۇٴৄ౥研৯LjԈઔ࠲၎ၟׯࣅ极ג

ۇٴޟბĂ܅ਖ਼ۇٴბĂUCSF ڪăഄዐ 11 ॆऐࠓਸቛට༹

研৯Ljഄ໲ྺۯ࿿研৯ăങৃྺኹLjᅙঢ়ᆶࡗג 600 ܠ

√ UCSF

√ UCSF 3T

√ Sunnybrook

√ MSKCC

√ MSKCC perclinical

√ NIH

√ U Maryland

√ Stanford

√ U Penn

√ UT Southwestern

√ MD Anderson

√ Washington U

√ Singapore Heart Center

√ CGMH Taiwan

√ Oxford University

√ University of Cambrideg MRIS

√ University of Cambrideg WBIC

√ Rigs Hospital Copenhagen

√ Aarhus University

√ ETH Zürich

√ Lublin

√ University of Nottingham

√ UCL London

√ Warsaw

√ University Hospital Tübingen

√ DKFZ Heidelberg

ටă၄ሞ全球ᆶ 30 ܠၜଣض๬֪ኟሞ৊ႜLj੗ᅜ֖९

ྪበLjClinicalTrials.govăժ൐全球ᄺႚׯକ Research

Circle 科研ංLjۨ೺ਉႜ঍ୁᇑݴၛă

US/Canada Europe Asia

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C13 超极化代谢成像学术委员会

26 ॆ C13 ג极ࣅ代谢磁共振ڦ๑ᆩኁׯࠓକᅃ߲

RCT ۇٴڦॆབྷăཞ้Ljᆶ 8 ࿋ሞ޿ଶᇘᆶጣศ෇研৯Lj

൐ਏᆶڦࡻ࢔ბຍں࿋ڦ๘হኪఁጆॆLjԥ GE ᄥ൩ׯ

૬କג极ࣅ代谢ׯၟ྿ᇵࣷăᇑ GE 共ཞฆᅱג极ࣅ代

谢ᆖၟڦ݀ቛݛၠᅜतׂ೗ᆫڦࣅႴ൱Ă磁共振रຍڦ

݀ቛڦႴ൱ڪڪăཞ้Ljኄ߲྿ᇵ࣏ࣷፔྺᅃ߲ጨศڦ

ࠥ࿚ཷ༹Ljྺ RCT ׯᇵ໯௬ଣڦ科研࿚༶؜కࣄ֧ă߸

ዘᄲڦLjኄ߲྿ᇵׯࣷᇵ਩ઠጲ全球ۥपڦ科研ऐࠓLj

ܸ൐໱்ڦ研৯ݛၠᄺᆶ໯փཞLj໱்਩ྺࡍᅅᇾ੗ᅜ

৊ႜࢇፕڦയሞࢇڦፕअӵăႴᄲኸ؜LjUCSF ڦ Dan

Vigneron ঞ๲๟ג极ࣅ C13 代谢ׯၟڦံൻᇑێएටLj

ᄺ๟ GE ፌ৆௢ࢇڦፕअӵă

UCSF ๟ణമ全球ሞגपࣅ 13C ݛ௬研৯ፌമᄂፌ全

ࢩݿྺଉLjᅜतፌ૰科研ڦࢩኮᅃLjᆛᆶፌႧܓྲཱྀڦ௬

ضଣഄᅙঢ়ሞࡕׯܠ࢔ڦၟׯ代谢ࣅ极ג ঢ়ᄓLjC13ڦ

全球科研文献集锦

C13 ג极ׯࣅ๟ၟႜᄽڦ݀ቛඤۅLj௅

౎݀՗ڦ࿔ቤࡗגଇӥೊLj၄ሞጺ共݀՗࿔

ቤᅙঢ়ࡗ 2000 ೊLjഄዐփ݄Ԉઔ NatureĂ

Science ۥڪप೺਽ݴߛڦ࿔ቤăԨກৈৈ

๭భକഄዐᅃևݴਏᆶ代՗Ⴀڦ࿔ቤLjᇑۇٴ

ăۅ科研ඤڦଶᇘࣅ极גၛ全球ሞݴॆ

Ԩກॽ࿔၅ׯݴ຺߲ևݴLjԈઔጹຎೊLj

዗ୀೊLj႐ე࠶ೊLjหঢ়ೊᅜतरຍݛ݆ೊă

ཚࡗለ܁࿔၅࿢்݀၄ 13C ג极ࣅरຍ๟ణ

മᆖၟბዐፌമᄂڦरຍLjܔᇀ࿄ઠڦ代谢

研৯ࢅਸቛᆖၟթ૙ბ研৯༵ࠃକᆶ૰ڦኤ

਍ࢅएإăణമ全球ᅙᆶ 700 ܠටْጀพࡗ

ג极ڦࣅ 13C եཛྷ໗Ljג极ࣅरຍጽၠଣض

ኸන੗ځă

ሞԨ集锦ዐ࿢்๭୤କ20ೊ࿔၅ᇱ࿔Lj

ժ൐௅ᅃೊ࿔ቤ࿢்ۼ৛႐ጚԢକ࿔၅ڞ

܁Ljړ඗Դኁ຤ೝᆶ၌ැᆶփፁኮتLj൩߳

࿋ጆॆ಼ೠኸኟă

മํᄓዐڟڥକڦࡻ࢔ॠᄓLjᅺُഄᄺ๟ NIH ዆ۨڦ

ăںಢჟएڦၟׯ代谢ࣅ极ג C13

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Biomedical Applications of the Dynamic

Nuclear Polarization and Parahydrogen Induced Polarization Techniques for Hyperpolarized 13C MR Imaging

综述简介

综述概览

] ࣅ极גᅏยԢ၄ጒĂࣅĂ极إஃए૙ࣅ极ڦၟׯࣅ极גକຎ߁ຎጹԨ

13C] եཛྷ໗ଣضമᆌᆩ研৯तଣض研৯യ૰त

৊ቛĂଣض๬ᄓ全球߁઄Ăႎ႙༑ኍ研৯৊ቛतᆌᆩă

· ࢃ ໎13C ڦ极ݛࣅ๕Ԉઔම঴ۯༀࢃ极ࣅ݆DŽd-DNPDžࢅዙൠᆻڞ极ࣅ݆DŽPHIPDžăSpinLab ๟एᇀ d-DNP ፌႎर

ຍߛڦཚଉ࿮ਪ极ࣅᅏLjփၩࡼᅂ࡜Ljሞ ~0.9 K ࢅ 5T ူ߾ፕLjࡀ׉इٳߛڥ 40% ڦ] 1-13C] եཛྷ໗极ࣅLj๟ങৃྺ

ኹྸᅃԥ಼ጚᆩᇀටૌᆌᆩڦဣཥኟሞ全球੺໏೵तժۇٴଉᆩᇀଣض研৯ዐă

· 代谢ᅴ׉๟ҵኢĂ႐ე࠶दթࢅ໱ഄदթڦՔኾLjᇑᄁኢࢅ௨ᅧݒᆌᆶጣాሞ૴ဣăଣݘ࠽ضᆌᆩࢃڦᅅბ

18F-FDG 代谢ׯၟփీీॠ֪༛ট঴ڼᅃօኮڦࢫ代谢ୟ০ăג极ࣅ] 13C] եཛྷ໗ሶ੗ᅜܔူᆴ代谢࿿ዊ৊ႜॠ֪Lj

๟代谢ׯၟݛ௬ଣضᆌᆩፌᆶമ཰ڦၭݴጱLj੗ᆩᇀ዗ୀĂ႐ሤĂۇٴస代谢ׯၟLj๟ਏᆶയ૰ڦ FDG-PET ଣض༻代

ӄăݛ

· 全球ᅙᆶࡗג 30 ၜג极ࣅ] 1-13C] եཛྷ໗ଣض๬ᄓDŽᅙྜׯĂኟሞ৊ႜځࢅ৊ႜڦጺࢅDžሞெࢅࡔ౹ዞጀ֩Ljኍܔ

ڥసևदթLjइഄ໱ࢅदթ࠶ᆶ႐ე࣏ҵLjޒೄࢅҵĂᅐ၇ҵࠆҵĂጱט୹दթԈઔമଚ၇ҵĂసҵĂළ၇ҵĂڦ

၎Բᇀ FDG-PET ৊ᅃօڦदթ႑တăᇨऺ࿄ઠब౎ኄᅃຕጴ࣏ॽ৊ᅃօሺेLjଣضገࣅ৊໏ेႜዐă

· أକ HP [1-13C] եཛྷ໗༑ኍኮྔLj࣏ᆶۇٴଉႎ႙ڦ༑ኍԥ研݀Lj༑໭ᆩᇀփཞթ૙࠵ڦײࡗִăԈઔג极ࣅ] 2-13C]

եཛྷ໗DŽෙ᷌໗თ࣍ాዐक़代谢࿿ೠࠚDžLj[1-13C] ౖ໎DŽ࠺ጀೠࠚDžLj[1,4-13C2] ޷க໗DŽဦԇ࣋ຶೠࠚDžLj[1-13C]

ྃൠੇ࣋ე໗ჸࢅ] 1-13C] ੇ࣋ე໗ჸDŽᄟ࣏ࣅᇱༀೠࠚDžLj[

13C] ༐໗ൠჸࢅ] 1,5-13C2] ா໗DŽpH ೠࠚDžLj[5-13C] ࠢ

ҽḅӃĂ [1-13C] ࠢҽ໗त [1- 13C]a- ཛྷ࿼ܾ໗DŽࠢҽḅӃாࢅࠢեገҽா代谢DžLj[U-13C] ೯༥༛DŽᅚḅޤா A 代谢Dž

ڪڪăᆶၳܠڦዖ༑ኍ共极ࣅํ၄੗ཞ้ॠ֪ܠ代谢ୟ০Ljइࢻڥցթ૙႑တă

· ዙൠᆻڞ极ࣅ๟ᆶയ૰ڦ极ࣅरຍLj极ࣅ੗ೝ຤থৎ d-DNPLjణമධتሞራ೺研݀঩܎Ljช࿄ᆶ؊ۯڦݴ࿿研৯ă

ኍܔ 15N ࢅ 19F גڦ极ࣅरຍᄺሞ༑໭ዐă

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Magnetic Resonance in Medical Sciences 1

Biomedical Applications of the Dynamic Nuclear

Polarization and Parahydrogen Induced Polarization

Techniques for Hyperpolarized 13C MR Imaging

Neil J. Stewart and Shingo Matsumoto*

Since the !rst pioneering report of hyperpolarized [1-13C]pyruvate magnetic resonance imaging (MRI) of

the Warburg e"ect in prostate cancer patients, clinical dissemination of the technique has been rapid; close

to 10 sites worldwide now possess a polarizer !t for the clinic, and more than 30 clinical trials, predominantly for oncological applications, are already registered on the US and European clinical trials databases.

Hyperpolarized 13C probes to study pathophysiological processes beyond the Warburg e"ect, including tricarboxylic acid cycle metabolism, intra-cellular pH and cellular necrosis have also been demonstrated in the

preclinical arena and are pending clinical translation, and the simultaneous injection of multiple co-polarized

agents is opening the door to high-sensitivity, multi-functional molecular MRI with a single dose. Here, we

review the biomedical applications to date of the two polarization methods that have been used for in vivo

hyperpolarized 13C molecular MRI; namely, dissolution dynamic nuclear polarization and parahydrogeninduced polarization. #e basic concept of hyperpolarization and the fundamental theory underpinning

these two key 13C hyperpolarization methods, along with recent technological advances that have facilitated

biomedical realization, are also covered.

Keywords: 13C metabolic MRI, dynamic nuclear polarization, hyperpolarization, molecular imaging,

parahydrogen-induced polarization

Published Online: December 27, 2019

Magn Reson Med Sci 2019; XX; XXX–XXX

doi:10.2463/mrms.rev.2019-0094

Division of Bioengineering and Bioinformatics, Graduate School of Information

Science and Technology, Hokkaido University, Hokkaido, Japan

*

Corresponding author: Division of Bioengineering and Bioinformatics, Graduate

School of Information Science and Technology, Hokkaido University, Sapporo

060-0814, Hokkaido, Japan. Phone: +81-11-706-6789, Fax: +81-11-706-6802,

E-mail: smatsumoto@ist.hokudai.ac.jp

©2019 Japanese Society for Magnetic Resonance in Medicine

This work is licensed under a Creative Commons Attribution-NonCommercialNoDerivatives International License.

Received: August 21, 2019 | Accepted: November 4, 2019

REVIEW

The frst in-man hyperpolarized [1-13C]pyruvate MRI exams

in patients with prostate cancer realized the potential for

observing metabolic processes beyond glycolysis, which is

typically probed by 1F-Àuorodeoxyglucose positron-emission

tomography (1F-FD*-P(T) until recently the only metabolic imaging method used routinely in the oncology clinic.4

This pioneering study has been followed by a rapid dissemination of HP [1-13C]pyruvate MRI for clinical applications,5

facilitated by the development of commercial, sterile polarization systems for clinical use.6

As of -une 219, more than

3 clinical trials worldwide pertaining to HP [1-13C]pyruvate

MRI are either in a complete, in progress, or pending phase

and this number is predicted to only increase further over the

coming years.

In this review article, we provide a brief overview of the

concept of hyperpolarization and the theory behind the

methods to obtain liquid-state 13C polarization namely,

dissolution dynamic nuclear polarization (d-DNP) and

parahydrogen-induced polarization (PHIP), followed by a

comprehensive review of the biomedical applications of HP 13C MRI by, with a particular focus on recent clinical MRI

applications of HP [1-13C]pyruvate and other hyperpolarized 13C molecular imaging probes with clinical promise.

Introduction

Hyperpolarization refers to a class of methods that enable

the fundamental sensitivity limits of magnetic resonance

imaging (MRI) to be overcome, allowing functional imaging

of exogenous agents of unprecedented quality.1 Over the

last 2 years, hyperpolarized (HP) 3He and 129;e noble gases

have been developed from experimental tools into safe,

inhalable contrast agents for high-resolution, functional MRI

of the lung airspaces and are already used routinely in a clinical setting.2

On the other hand, HP 13C-labelled liquid-phase

probes for molecular and metabolic MRI hold great promise

for interrogating pathophysiology at the cellular level.3

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N.J. Stewart et al.

2 Magnetic Resonance in Medical Sciences

Theoretical Background

Hyperpolarization

When placed in a magnetic feld B, spin-ò nuclei of gyromagnetic ratio g occupy one of two =eeman states at energies

±g !B2. The nuclear spin ³polarization´ is defned as the

fractional difference in the population of the two states,

which under conditions of thermal equilibrium is derived

from the %oltzmann distribution

P h E

k T

B

B B k T = æ

è

ç ö

ø

÷ æ

è

ç ö

ø

÷ tan D » 2 2

0 g ! (1)

The %oltzmann (thermal) polarization of 13C²the only

stable spin-ò carbon nucleus²at typical clinical magnetic feld

strengths is a1í. In fact, MR of endogenous 13C is challenging

not just due to its afourfold lower gyromagnetic ratio than 1H

the natural abundance of 13C is only 1.1 and thus sensitivity is

poor. A a1-fold MR signal enhancement can be obtained on

endogenous tracers through 13C-labeling, and a further 4–5

orders of magnitude enhancement via hyperpolarization.

Hyperpolarization denotes a temporary state of dramatic

population excess in one nuclear spin state (see Fig. 1) and can

be realized by a number of approaches brute force polarization (utilizing low temperatures and high magnetic felds to

directly increase the nuclear polarization), spin-exchange

optical pumping9 and metastability-exchange optical

pumping1 for hyperpolarized gases and d-DNP11 and PHIP12

for solution-state 13C applications. The latter two methods

have been demonstrated for biomedical 13C molecular MRI

applications and these form the focus of this review article. We

note that signal amplifcation by reversible exchange

(SA%R(),13 closely-related to conventional PHIP, is recently

showing progress toward potential in vivo application14 but

will not be covered in this article as biomedical application is

yet to be shown we refer the reader to Robertson and Mewis15

for an up-to-date review.

The MR signal enhancement associated with hyperpolarization is not permanent longitudinal relaxation acts to

return the nuclear spin state populations to that of thermal

equilibrium, and after radiofrequency excitation, the hyperpolarized state is not recovered.1 Research into generating

so-called ³long-lived´ states and also generation of continuously re-hyperpolarization1 are an active felds1 however,

hyperpolarized [1-13C]pyruvate, the most promising molecule for clinical applications, remains limited by a T1 a  s.

The decay in magnetization associated with a number of RF

excitations n with repetition time TR and Àip angle a can be

described as follows

M n M n TR

T xy n j

j

n

( ) = - exp ( - ) sin ( ) cos ( ) é

ë

ê ù

û

ú =

-

0 Õ 1 1

1

1 a a (2)

For a constant Àip angle, and TR << T1, (quation (2) can

be simplifed to M n xy

n ( ) = sin ( ) cos ( ) - M01 a a [for example,

after N 12 RF excitations at Àip angle ƒ a magnetization of

only M N xy ( ) » ° 0 3. s M in ( ) 8 0 remains]. The signal decay

during acquisition leads to fltering of the k-space and image

blurring, but which can be somewhat compensated for by

modifying the Àip angle throughout the acquisition process.1,19 Nevertheless, acquisition of hyperpolarized signals

necessitates effcient encoding of k-space, such as with spiral

trajectories,2 parallel imaging21 or compressed sensing.22

Hyperpolarized 13C metabolic MRI relies upon the discrimination of MR signals from the injected probe (e.g. pyruvate) and

its metabolic products (e.g. lactate) by chemical shift. If spatial

information is not essential, dynamic spectroscopy is a simple

and robust means to probe metabolism dynamics.23 Several

imaging strategies have been developed24 including phaseencoded chemical shift imaging (CSI).25 which although ineffcient, allows acquisition of full spectra echo planar

spectroscopic imaging, in which (usually Ày-back) gradients

are used for simultaneous 1D spatial encoding and spectral

readout, permitting several-fold acceleration at the expense of

SNR2,2 spiral chemical shift imaging, wherein multi-dimensional spatial data is encoded simultaneously with spectral

data in a similar manner to tomosynthesis2 spiral encoding

schemes29 combined with the robust iterative decomposition

with echo asymmetry and least-squares estimation technique3

and spectral-spatial excitation for additional effciency and the

Àexibility of a different Àip angle on each resonance of

interest.31 In light of the long T2 of 13C in vivo, SNR benefts

have been realized by using single or multi-echo balanced

steady-state free precession.32,33

Fig. 1 Concept of hyperpolarization. (a) The occupation of nuclear

Zeeman states of a spin-½ system in thermal equilibrium in a magnetic field follows that of the Boltzmann distribution [cf. Equation

(1)]; for 13C at 1.5T and 300 K, the polarization, i.e. the population difference between the spin up and down states for 13C is

only P ~ 10−6. (b) Hyperpolarization describes the state of a large

excess population in one of the nuclear Zeeman states, leading to

a nuclear polarization several orders of magnitude greater than the

Boltzmann polarization (Data is reproduced from the original dissolution dynamic nuclear polarization (d-DNP) paper11 (Copyright

(2003) National Academy of Sciences, USA) and compares NMR

spectra obtained from thermally-polarized and hyperpolarized 13C

urea of ~60 mM concentration).

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Biomedical Applications of HP 13C MRI

Epub ahead of print 3

Dynamic nuclear polarization

Dissolution dynamic nuclear polarization²to date the principal polarization techniques employed to generate hyperpolarized [1-13C]pyruvate²relies upon the relatively large

electron gyromagnetic ratio ( ) g g e P » 660 which [according

to (quation (1)] leads to an electron %oltzmann polarization

of approximately unity at temperatures a1 . at high feld

(see Fig. 2a).34 An effcient electron paramagnetic agent (free

radical, see e.g. /umata et al.35) is mixed with a glassing

agent and the target probe to be polarized (e.g. pyruvate),

which is cooled to a1 . under a magnetic feld of several

tesla. In the subsequent glassy solid state where d-DNP is

most effcient, microwave irradiation is used to induce polarization transfer from free electrons to 13C nuclei over the

course of a1 h. At temperatures 4.2 ., polarization transfer

is believed to be primarily driven by the thermal mixing

effect,3 though depending on exact experimental conditions,

contributions from the so-called solid effect and cross

effect,3 and the Overhauser effect in the solution phase,3

may not be ignored. After polarization transfer, the frozen

sample is rapidly dissolved in a superheated solvent and

transferred to the MRI system for measurement [hence the

term ³dissolution (d)´11].

The frst commercial d-DNP system for preclinical

research applications shortly followed the publication of

the original d-DNP paper11 (HyperSense, Oxford Instruments, 8.) and other effcient research systems have since

been developed.39 Most d-DNP systems including the

HyperSense require large quantities of liquid helium to

maintain the low sample temperature however, two recent

landmark developments have enabled d-DNP without consumption of cryogens a high-throughput, sterile polarizer

for clinical applications Spin/ab6 (*( Healthcare,

Waukesha, WI, 8SA), and an effcient research polarizer

with variable magnetic feld (the SpinAligner, (Polarize,

Frederiksberg, Denmark)),4 both of which are commercially available. The Spin/ab (Fig. 2a), operating at a.9 .

and 5T and routinely obtaining up to 4 [1-13C]pyruvate

polarization, is the only system to date approved for human

application.

Fig. 2 Concept diagram for dissolution dynamic nuclear polarization

(d-DNP) and parahydrogen-induced

polarization (PHIP) polarization techniques. (a) In d-DNP, the source of 13C

nuclear polarization (P) is the approximately unity electron polarization (P)

at low temperature and high magnetic

field (curves plotted for 3.35T) (i). This

is transferred to 13C via microwave

excitation (ii), predominantly mediated via the thermal mixing effect. (iii)

Prototype commercial cryogen-free

d-DNP system reported in ArdenkjaerLarsen et al.40 (original photo courtesy of Jan Henrik Ardenkjaer-Larsen,

Technical University of Denmark and

GE Healthcare). (b) In PHIP, the source

of 13C polarization is the inherent spin

order of the parahydrogen spin isomer

of hydrogen, which can be generated

to very high purity by cooling normal

hydrogen in the presence of a paramagnetic catalyst (i). Parahydrogen is

reacted with an unsaturated substrate,

generating 1H hyperpolarization, which

is subsequently transferred to 13C or

other target heteronucleus (ii). Several

dedicated low-field (mT) polarization

systems have been designed for automating the hydrogenation and polarization transfer processes; the example

shown is reprinted with permission

from Springer Nature (Hövener et al).58

i)

ii)

iii)

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N.J. Stewart et al.

4 Magnetic Resonance in Medical Sciences

Parahydrogen-induced polarization

Despite surmounting the hurdle associated with cryogen consumption, the initial outlay required for d-DNP systems

remains high (aseveral million 8SD for the Spin/ab). PHIP12

is a relatively recent technique that offers a cheaper route to

hyperpolarized 13C molecules for biomedical MRI applications.41 PHIP relies on the inherent spin order of parahydrogen, a spin isomer of hydrogen. At room temperature, the

two spin-ò nuclei of each hydrogen molecule have an equal

probability to occupy one of four spin states three states of

total spin 1 (orthohydrogen, ³triplet´ state) and one state of

total spin  (parahydrogen, ³singlet´ state). When cooled in

the presence of a paramagnetic catalyst (typically iron(III)

oxide or charcoal, which promotes the otherwise slow

symmetry-forbidden transition between orthohydrogen and

the lower energy parahydrogen state) to a2 ., a parahydrogen fraction of a1 can be obtained (see Fig. 2b).

Parahydrogen itself is NMR silent since it has a total

nuclear spin of  however, upon pairwise addition to

magnetically-inequivalent sites on an unsaturated substrate

molecule, the symmetry of the parahydrogen singlet state is

broken and hyperpolarized 1H MR signals can be observed.

This hydrogenation reaction is typically performed in an

organic solvent or the aqueous phase in the presence of a

transition metal (typically Rh- or Ru-)based catalyst.42 The

resulting 1H nuclear spin state depends on the magnetic feld

at which parahydrogen addition is performed at high feld,

e.g. within the MR system itself, the parahydrogen and synthesis allow dramatically enhanced nuclear alignment effect

is observed,12 whilst for hydrogenation at low feld followed

by adiabatic transport of the sample to the MR system for

detection, the adiabatic longitudinal transport after dissociation engenders nuclear alignment effect is observed.43 Several studies using PHIP of 1

H nuclei have been performed

(e.g. to generate --coupling derived contrast44 and gas-phase

imaging45) however, due to the large background signal

in vivo and lack of attainable pathophysiological functional

information such as that pertaining to metabolism, heteronuclei such as 13C or 15N are of greater interest for biomedical

applications. Polarization transfer from 1H to heteronuclei is

mediated by spin–spin couplings and can be driven by specialized RF pulse sequences4–4 or by subjecting the sample

to a magnetic feld cycle.49–51 The selection of polarization

transfer method and its parameters depends on the confguration of the target molecular probe.52,53

Regarding hardware, parahydrogen enrichment of a5

can be achieved by simply Àowing hydrogen gas through a

cryogenic tube submersed in liquid nitrogen.54 A highthroughput system to generate and store up to 5 bar of 9

parahydrogen has been developed for biomedical applications55 once stored, parahydrogen enrichment can be maintained for months provided that paramagnetic molecular

oxygen is not present.56 Several automated PHIP polarizers

for low-feld hydrogenation and polarization transfer have

been developed5–59 incorporating heated, high-pressure

spray reactors however, promising results have also been

obtained by simply shaking or bubbling of a parahydrogenflled NMR tube followed by feld cycling by hand (see e.g.

Chukanov et al.). In addition, unlike d-DNP, it is possible to

perform both the hydrogenation reaction and polarization

transfer and generate heteronuclear hyperpolarization within

the NMR magnet itself, minimizing the time for polarization

decay.4,1

d-DNP-polarized [1-13C]pyruvate: the pathway to

clinical application

Abnormal metabolism is a hallmark of cancer, cardiovascular disease and other pathologies, and is intrinsically linked

to inÀammation and immune response.2 1F Àuorodeoxyglucose (FD*), a glucose analog, is routinely used for highsensitivity and specifcity clinical P(T imaging of glucose

metabolism3 and is the recommended clinical indicator for

head, neck, lung and pancreatic cancer.64 However, since

FD*--phosphate does not undergo further glycolysis, FD*-

P(T cannot probe metabolism beyond the frst step of the

glycolysis pathway. In this respect, d-DNP of [1-13C]pyruvate represents a signifcant development permitting unprecedented access to downstream metabolites to further aid

understanding of cancer and disease mechanisms.

Whilst the frst in vivo studies of a molecule polarization

by d-DNP were performed with HP 13C-urea,65 it was quickly

realized that [1-13C]pyruvate, which plays a critical role in

metabolism (see Fig. 3), is an ideal molecule for d-DNP since

it is self-glassy and has long T1 for 13C at the 1 and 2 positions

(a4– s).66 *olman et al.67 demonstrated the frst real-time

metabolic imaging of metabolic production of [1-13C]lactate,

[1-13C]alanine and [1-13C]bicarbonate from hyperpolarized

[1-13C]pyruvate in healthy rats and pigs, and demonstrated differences in metabolite signal intensity in tumor tissues. In

cancer cells, glycolysis prevails over oxidative phosphorylation and the conversion of pyruvate to lactate via lactate dehydrogenase is up-regulated this is known as the Warburg

effect.9 To date, increased HP [1-13C]pyruvate to [1-13C]lactate conversion has been used as the principal outcome of HP

[1-13C]pyruvate MRI studies in several types of cancers.,–3

The high sensitivity of HP [1-13C]pyruvate MRI affords the

possibility of non-invasive assessment of cancer treatment

response, frst demonstrated by Day et al.,74 who showed a

decrease in of HP 13C pyruvate–lactate Àux after chemotherapy.

The technique has since been applied in several studies of radiotherapy response5, and assessment of other treatments,

and reported to present a viable clinical alternative to FD*-

P(T for early tumor response in a preclinical study.9

In a landmark paper, Nelson et al. reported the utilization

of *(¶s prototype sterile d-DNP system6 to perform the frst

in-man HP [1-13C]pyruvate MR spectroscopy and imaging

feasibility study of patients with prostate cancer,4 demonstrating distinction of high- and low-grade tumors. This

development has opened the door to realize real-time clinical

metabolic imaging with HP [1-13C]pyruvate and the rapid

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Biomedical Applications of HP 13C MRI

Epub ahead of print 5

uptake of the technology is epitomized by the fact that more

than 2 *( Spin/ab polarizers have been installed worldwide,

with close to half presently in use for human studies. First

reports of the application of [1-13C]pyruvate to study metabolism in the healthy human heart and brain1 have reported

good tolerance of the procedure and contributed valuable reference data for interpretation of patient studies. In prostate

cancer, HP [1-13C]pyruvate has been shown to detect early

response to androgen deprivation therapy with a sensitivity

exceeding that of T2- and diffusion-weighted MRI.2 Preliminary reports in patients with liver metastases3 and those with

brain tumors4,5 demonstrate the wide range of potential targets of the technology and provide important pilot data for

future trials. Several of these early clinical results are summarized in Fig. 4. Furthermore, at the 219 International

Society for Magnetic Resonance in Medicine (ISMRM)

meeting, frst HP [1-13C]pyruvate data in human patients

with breast cancer, in which the relationship between intertumoral heterogeneity and gene expression analysis was investigated, and preliminary longitudinal HP [1-13C]pyruvate

data in glioma patients, was reported, highlighting the

advantages of the non-invasive nature of the technique for

short- and long-term patient follow-up. Moreover, more than

3 clinical trials (sum of completed, ongoing and pending

trials) are registered on the 8S and (uropean clinical trials

registries (summarized in Table 1) targeting a range of

conditions, including prostate, brain, breast, ovarian, uterine,

pancreatic and skin cancers, in addition to cardiovascular

indications and other brain pathologies. Comparison with

FD*-P(T to further comprehend the complementary information that can be obtained9,9 is a critical next step to aid

interpretation of human HP [1-13C]pyruvate data and

encourage further clinical dissemination.

As the number of clinical studies with [1-13C]pyruvate

increases, there is a growing need for robust quantitation

methods that can be applied universally for multi-site validation studies.91 Typically, HP [1-13C]pyruvate MR examinations include dynamic spectroscopy of the time-course of

metabolic conversion of pyruvate, in addition to imaging.

Semi-quantitative analysis of metabolic dynamics measured

by MR spectroscopy can be performed using one of several

models that have been developed to describe the rate of pyruvate–lactate conversion kPL.

92 For the most simple two-compartment model of pyruvate-lactate conversion, written in

matrix form (see e.g. Harrison et al.92 and Harris et al.93)

d

dt

P

L

k

k

k

k

P

L

z

z

PL P

PL

LP

LP L

z

z

é

ë

ê ù

û

ú = - -

- -

é

ë

ê ù

û

ú

é

ë

ê ù

û

ú

r

r

(3)

where PZ and LZ are the z-magnetization of pyruvate and lactate, respectively, kLP is the (reverse) lactate–pyruvate conversion rate and r a i i = - 1 T1 / log (cos( )) / , TR describes

T1 relaxation and RF-induced depolarization [cf. (quation

(2)]. This equation can be analytically74 or numerically

solved and utilized to ft the magnetic resonance spectroscopy

Fig. 3 Schematic of glycolysis,

pyruvate metabolism to alanine

and lactate, and the tricarboxylic

acid (TCA) cycle within the mitochondria. Green circles: products

of [1-13C]pyruvate; red triangles:

products of [2-13C]pyruvate.

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(MRS) signal intensities of lactate and pyruvate (see for

example the data in Fig. 4a) to yield kPL as a metric of the

Warburg effect. Model-free approaches such as the area

under the signal-time curve and time-to-peak present simple,

robust alternatives.91 CSI-based techniques yield individual

images for each metabolic product, and ratio maps of lactate

to pyruvate signal intensity are commonly used to provide

some degree of quantitation in a regional manner.

d-DNP beyond [1-13C]pyruvate: other candidate

molecular probes

The range of molecular imaging targets that can be polarized

by d-DNP is vast and an exhaustive list94 is beyond the scope

of the present article. In the following, we introduce several of

the most promising d-DNP-polarizable 13C molecular probes

for biomedical applications (see Table 2 for a summary).

While the large majority of pre-clinical and clinical

studies to date have exploited the sensitivity of HP [1-13C]

pyruvate to the Warburg effect (i.e. pyruvate–lactate metabolism), the C1 atom of the remaining pyruvate that enters into

the mitochondria is oxidized to CO2 and subsequently converted to bicarbonate, and thus cannot be used to probe tricarboxylic acid (TCA) cycle metabolism. However, the C2

atom passes to acetyl-CoA and enters into the TCA cycle,

exhibiting several metabolic fates (Figs. 3 and 5b). Schroeder

et al.23 frst reported detection of downstream metabolites

including [1-13C]acetylcarnitine, [1-13C]citrate, [5-13C]glutamate in perfused rat hearts after injection of HP [2-13C]pyruvate, with decreased citrate and glutamate production

post-ischemia. In response to rapid pacing challenge, in vivo

measurements of cardiac metabolism showed increased

[5-13C]glutamate production,95 and increased glutamate,

Fig. 4 Clinical examples of hyperpolarized [1-13C]pyruvate MRI. (a) Representative dynamic 13C MRS data of pyruvate and lactate signal

in prostate cancer region and contralateral prostate region of a prostate cancer patient, and lactate/pyruvate signal ratio map overlaid

on a T2-weighted 1H MR image (adapted from Figs. 2 and 4, respectively of Nelson et al.4 reprinted with permission from the American

Association for the Advancement of Science (AAAS)). (b) HP [1-13C]pyruvate, lactate and bicarbonate MR images and a non-selective MR

spectrum of the healthy human heart (adapted from Figs. 1 and 3, respectively of Cunningham et al.80 reprinted with permission from

Wolters Klumer Health, Inc). (c) Comparison of HP [1-13C]pyruvate and lactate MR images to contrast-enhanced T1-weighted MRI and

perfusion plasma volume mapping in a patient with recurrent glioblastoma (adapted from Fig. 4 of Miloushev et al.85 permission from the

American Association for Cancer Research (AACR)).

a

b c

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Table 1 Summary of ongoing clinical trials pertaining to hyperpolarized 13C MRI (from clinicaltrials.gov, clinicaltrialsregister.eu and drks.de, accessed on 2019/06/12)

Primary condition

(number of trials) Participating center (country) Enrollment†

Brain cancer6 Sunnybrook Health Sciences Centre, Toronto (Canada) 121

UT Southwestern Medical Center, Dallas (USA) 44

M D Anderson Cancer Center, Dallas (USA) 13

University of California San Francisco, San Francisco (USA) 80

UCSF Helen Diller Family Comprehensive Cancer Center, San

Francisco (USA)

9

Uterine and ovarian cancer2 Sunnybrook Health Sciences Centre, Toronto (Canada) 10

Addenbrooke’s Hospital, Cambridge (UK) 40

Breast cancer2 UT Southwestern - Advanced Imaging Research Center, Dallas (USA) 110

Sunnybrook Health Sciences Centre, Toronto (Canada) 13

Traumatic brain injury and

CNS tumors2

UT Southwestern Medical Center, Dallas (USA) 16

Stanford University School of Medicine, Palo Alto (USA) 10

Other: Sarcoma1 Advanced Imaging Research Center, Dallas (USA) 20

Fatty liver1 UT Southwestern Medical Center, Dallas (USA) 16

Pancreatic cancer1 Aarhus University Hospital, Aarhus (Denmark) 15

Skin cancer1 Aarhus University Hospital, Aarhus (Denmark) 30

General cancer1 Memorial Sloan Kettering Cancer Center, New York (USA) 84

Prostate cancer9 University of California San Francisco, San Francisco (USA) 261

Sunnybrook Health Sciences Centre, Toronto (Canada) 40

M D Anderson Cancer Center, Dallas (USA) 10

Cardiovascular disease5 UT Southwestern Medical Center, Dallas (USA) 10

Sunnybrook Health Sciences Centre, Toronto (Canada) 112

University College London, London (UK) 25

University Hospital Zurich, Zurich (Switzerland) 50

Aarhus University Hospital, Aarhus (Denmark) 20

Enrollment: approximate patient numbers scanned or anticipated (in cases of multiple studies at the same center, enrollment

represents a summation of the enrollment for each individual study).

Table 2 Non-exhaustive list of 13C MR molecular probes polarizable by dynamic nuclear polarization (adapted with the publisher’s

permission from Table 1 of Hurd et al.163) and their chemical shift (and literature reference)

HP 13C probe (chemical shift) Metabolic products (chemical shift) Biomedical applications

[1-13C]Pyruvate (173 ppm)164 [1-13C]Lactate (185 ppm), [1-13C]alanine (178 ppm),

[1-13C]bicarbonate (162 ppm), [1-13C]pyruvate hydrate

(181 ppm)164

Warburg effect (cancer)

[2-13C]Pyruvate (208 ppm)96 [2-13C]Lactate (71 ppm),96 [2-13C]alanine (53 ppm),

[1-13C]citrate (180–181 ppm),165 [5-13C]glutamate

(184 ppm), [1-13C]acetylcarnitine (175 ppm), [3-13C]

acetoacetate (177 ppm)96

Tricarboxylic acid (TCA)

cycle metabolism

13C-Urea (162.5 ppm)100 None (end product) Perfusion

[1,4-13C2]Fumarate (175.4 ppm)103 [1-13C]Malate (181.8 ppm), [4-13C]Malate (180.6 ppm)103 Cellular necrosis

[1-13C] Dehydroascorbate (174.0 ppm)109 [1-13C]Ascorbic acid (vitamin C) (177.8 ppm)109 Redox status

13C-Bicarbonate (161 ppm)113 Carbon dioxide (125 ppm)113 pH mapping

[1,5-13C2]Zymonic acid (ppmurea + 10–15 ppm)116* None

[5-13C]Glutamine (178.5 ppm)166 [5-13C]Glutamate (181.5 ppm)166 Glutaminase metabolism,

[1-13C]a-ketoglutarate (172.6 ppm)117 [1-13C]Glutamate (177.5 ppm)117 TCA cycle metabolism

[1-13C]Acetate (182.5 ppm)120 [1-13C]Acetylcarnitine (202.1 ppm)120 Acetyl-CoA synthetase

activity

*

pH-dependent chemical shift.

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acetoacetate and acetylcarnitine production was observed

post-injection of an anti-cancer agent in rats.9 The frst clinical MR spectroscopy and imaging data of HP [2-13C]pyruvate in the healthy human brain was reported at the 219

ISMRM meeting9 however, application of the probe

remains challenging due to the relatively low concentration

of downstream metabolites generated in one study, none

were detectable.66

[1-13C]urea, the frst hyperpolarized 13C molecular MR

imaging agent demonstrated by the d-DNP method,11 is metabolically inert and shows promise as a HP MRI agent for

perfusion assessment.9,99 Furthermore, [1-13C]urea can be

co-polarized with [1-13C]pyruvate for simultaneous assessment of metabolism and perfusion,1 and co-labeling with 15N2 exhibits prolonged 13C relaxation times and improved

SNR11 facilitating for example the investigation of renal

functional changes.12

[1,4-13C2]fumarate can be hyperpolarized by d-DNP and

the rate of its conversion to malate, catalyzed by fumarase, is

indicative of cellular necrosis.13 HP [1,4-13C2]fumarate

exhibits high sensitivity to necrosis in myocardial infarction14 and acute kidney injury15 among other tissue pathologies, is complementary to [1-13C]pyruvate in the assessment

of treatment response (Fig. 5a) in breast cancer1 and effcient co-polarization schemes offer simultaneous probing of

multiple metabolic pathways.1

Hyperpolarization of the reduced and oxidized forms of

vitamin C²namely [1-13C]dehydroascorbate and [1-13C]

ascorbate, respectively²offers a novel means to probe intracellular redox status, a critical factor in normal and abnormal

cellular function.1,19 High concentrations of [1-13C]ascorbate can be observed post-injection of [1-13C]dehydroascorbate, and reduced HP [1-13C]ascorbate signal has been

utilized as an MR biomarker of renal oxidative stress.11,111

Several HP 13C-based molecular probes have been proposed for measurement of pH,112 a critical physiological factor.

In particular, injection of hyperpolarized 13C-bicarbonate and

monitoring of its conversion to 13CO2 has been proposed to

monitor pH113 and demonstrates sensitivity to abnormal pH in

cancer113 and ischemic heart disease.114 An alternative method

involves monitoring the HP 13CO2 production from injected

[1-13C]pyruvate.115 Recently, HP [1,5-13 C2]zymonic acid has

been proposed for high-sensitivity in vivo pH mapping, exhibiting a pH-sensitive chemical shift and T1 benefts over [1-13C]

bicarbonate.11

To probe glutaminase and alanine transaminase metabolism, respectively, HP [5-13C]glutamine and [1-13C]glutamate have been investigated. Conversion of injected HP

[1-13C]a-ketoglutarate to [1-13C]glutamate has been proposed as a potential biomarker of isocitrate dehydrogenase 1

gene mutations in glioma.11 Although the longitudinal relaxation of 13C nuclear spins in the glucose molecule is extremely

short, perdeuteration has facilitated studies of glycolysis

using HP [8-13C]glucose in cells11 and in vivo.

119 The action

of acetyl-CoA synthetase in generating acetyl-CoA²a

crucial molecule in fatty acid synthesis and TCA cycle

metabolism²has been investigated with HP [1-13C]acetate

in the heart12,121 and skeletal muscle.122

PHIP: candidate 13C molecular and metabolic

MRI probes

The choice of molecular probes for conventional hydrogenative PHIP is fundamentally limited by the requirement of an

unsaturated precursor substrate (i.e. a molecule containing a

double or triple bond to which parahydrogen is added to

yield the hyperpolarized probe).123 Nevertheless, a number

of promising HP 13C probes for biomedical MR applications

can be produced with a polarization level comparable to or

approaching that of d-DNP. Some of these are highlighted in

the following text and also in Table 3 for an exhaustive list,

we refer the reader to H|vener et al.41.

To date some of the most promising probes for metabolic

MRI by PHIP are based on succinate and its derivatives

(Fig. ), the metabolic activity of which was introduced earlier. Hyperpolarized [1-13C]succinate can be generated by

one of two PHIP strategies two-step parahydrogen addition,

frst to [1-13C]acetylenedicarboxylate (ADC) to yield [1-13C]

maleate, to which parahydrogen is added again to yield

[1-13C]succinate124 or by single-step parahydrogen addition

to [1-13C]fumarate.125,12 The latter method offers a prolonged [1-13C]succinate polarization lifetime, particularly if

deuterated fumarate is used, and also reduces the risk of

undesired injection of ADC, which is mildly toxic, and also

the intermediate (maleate).125 Whilst initial in vivo experiments in the rat brain did not exhibit clear metabolic conversion of PHIP-polarized [1-13C]succinate,124 the second

hydrogenation approach enabled detection of downstream

TCA cycle metabolites in a murine tumor model.12

Furthermore, the diethyl ester of [1-13C]succinate, derived by

parahydrogen addition of diethyl[1-13C]fumarate, appears to

exhibit some TCA cycle metabolic sensitivity and was shown

to distinguish murine tumor characteristics.12,12

Hyperpolarized hydroxyethyl [1-13C]propionate, produced

by parahydrogen addition of hydroxyethyl[1-13C]acrylate

(H(A), presents a potential high-sensitivity PHIP contrast

agent for angiography applications.5,12,129 In a recent study, the

entire process of parahydrogen addition to H(A followed by

polarization transfer, injection and in vivo MRI detection of

H(P was realized within an MRI system, i.e. without the

requirement of an external polarizer.13 Since 2-hydroxyethyl[1- 13C]propionate is easily polarized by PHIP and has strong, welldefned heteronuclear spin–spin couplings, it has also been

utilized to validate several novel techniques for optimization of

polarization transfer between parahydrogen and 13C.5,131,132

Hyperpolarized tetraÀuoropropyl[1-13C]propionate (TFPP)

can be derived parahydrogen addition of the corresponding

acrylate precursor and subsequent polarization transfer, and

has been proposed as a ³targeted´ molecular agent for interrogating lipid-rich atherosclerotic plaques.133 However,

whilst HP 13C-H(P and 13C-succinate can be generated in the

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Fig. 5 Pre-clinical MRI examples of promising HP 13C probes other than [1-13C]pyruvate. (a) HP 13C chemical shift imaging (CSI) of cellular necrosis pre- and post-etoposide treatment (increased necrosis) in a murine tumor model after HP [1,4-13C2]fumarate injection, and 13C MR spectra obtained from murine lymphoma cells; (i) untreated, (ii) post-etoposide treatment, (iii) lysed cells, demonstrating a strong

relationship between malate production and necrosis (adapted from Figs. 1 and 4 of Gallagher et al.103 with the publisher’s permission).

(b) CSI-derived maps and accompanying spectra of metabolites derived from mitochondrial metabolism after injection of [2-13C]pyruvate

into a healthy rat, exhibiting [1-13C]acetyl carnitine and tricarboxylic acid (TCA) cycle-derived [5-13C]glutamate resonances (adapted with

the publisher’s permission from Park et al.167). Results obtained pre- and post-injection of dichloroacetate (DCA), a proposed anti-cancer

drug used to influence acetyl-CoA production by modulating pyruvate dehydrogenase, are shown.

a

b

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Table 3 Non-exhaustive list of 13C MR molecular probes polarizable by parahydrogen-induced polarization (adapted with the

publisher’s permission from Table 1 of Hövener et al.41 and their chemical shift (and literature reference†

)

HP 13C precursor Hydrogenation products Biomedical applications

[1-13C]Acetyl dicarboxylic acid (151.6 ppm)155 [1-13C]Maleate (160 ppm) → [1-13C]Succinate (175 ppm)124 Tricarboxylic acid (TCA)

cycle metabolism [1-13C]Fumarate (166.5 ppm)155 [1-13C]Succinate (175 ppm)124

Diethyl[1-13C]fumarate (167.4 ppm)127 Diethyl[1-13C]succinate (175.8 ppm)127 TCA cycle metabolism

13C-Hydroxyethyl-acrylate 13C-Hydroxyethylpropionate (~180 ppm)50 Angiography

Tetrafluoropropyl[1-13C]acrylate Tetrafluoropropyl[1-13C]propionate (174 and 177 ppm)133 Atheromatous plaques

[1-13C]Phosphoenol-pyruvate (171.9 ppm)135 [1-13C]Phospholactate → [1-13C]Lactate (182.1 ppm)135 Gluconeogenesis, lactate

dehydrogenase metabolism

Propargyl[1-13C]pyruvate

(160 ppm)60

Allyl[1-13C]pyruvate (160.5 ppm)60 → [1-13C]pyruvate

(173 ppm) after hydrolysis

Warburg effect (cancer)

Vinyl[1-13C]acetate

(168 ppm)60

Ethyl[1-13C]acetate (174 ppm)147 → [1-13C]acetate

(182.5 ppm) after hydrolysis

Acetyl-CoA synthetase

activity

Chemical shift values only quoted for the particular solvent in the literature reference cited.

Fig. 6 In vivo magnetic resonance imaging (MRI) application of several hyperpolarized 13C probes generated by parahydrogen-induced

polarization (PHIP). (a) MRI angiogram of HP 13C-labeled malate dimethyl ester with corresponding 1H spin echo reference image of a

healthy rat (adapted with permission from Golman et al.49). (b) Chemical shift imaging (CSI) of HP diethyl [1-13C]succinate in a murine

model of renal cell carcinoma (reproduced from Zacharias et al.126 under the Creative Commons Attribution License). The 13C spectrum

corresponding to the pixel indicated by the white square shows tricarboxylic acid (TCA) cycle metabolism of diethyl succinate (DES) to

succinate (SUC) and fumarate (FUM). (c) Representative HP tetrafluoropropyl [1-13C]propionate (TFPP) fast imaging with steady-state

precession (FISP) image overlaid on a 1H RARE image, and HP 13C-TFPP spectra obtained from low density lipoprotein receptor (LDLR)

deficient mice compared with control mice, demonstrating excess lipid in LDLR mice (reproduced from Bhattacharya et al.133 with the

publisher’s permission).

a b c

pure aqueous phase using a water-soluble catalyst, TFPP

requires a high dose of ethanol as a co-solvent, limiting

potential in vivo applications.133

Since [1-13C]ethyl pyruvate ester has been shown to be

polarizable by d-DNP and shows some promise in comparison to [1-13C]pyruvate for functional brain imaging

applications,134 the hydrogenation precursor [1-13C]vinyl

pyruvate is an interesting potential target for PHIP, however

an effcient synthesis route remains elusive.

Shchepin et al.135 have proposed [1-13C]phospholactate, the hydrogenation product of [1-13C]phosphoenolpyruvate, as a possible route to HP [1-13C]lactate in vivo, which

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is subsequently taken up by tumors and several critical

organs.59,13 The hydrogenation reaction can relatively

easily be performed in water,13 which holds promise for

future biomedical studies.

(ster derivatives of 13C-glucose have been demonstrated

to be polarizable by PHIP13 however, the short polarization

lifetime (as) must be overcome (e.g. by deuteration) to facilitate

the realization of in vivo glycolysis measurement by PHIP of

glucose derivatives and the possibility of corroboration

against FD*-P(T.

Alteration of choline metabolism is a hallmark of tumor

progression, and several groups have investigated choline

precursors as potential molecular probes for PHIP.139,14

Rather than 13C, 15N-labeling can be used although 15N possesses an intrinsically low gyromagnetic ratio and hence sensitivity compared with 13C, extremely long relaxation times

can be realized, enabling metabolism dynamics to be followed over the course of several minutes. In particular, the

recent demonstration of 12 15N polarization with a lifetime

of over 2 min on a choline derivative is of interest for

in vivo cancer metabolism applications.141

Side-arm hydrogenation (PHIP-SAH):

a route to HP [1-13C]pyruvate

The majority of the above-mentioned probes offer only limited

or no metabolic information of suffcient sensitivity compared

with [1-13C]pyruvate produced by d-DNP however, the lack

of a suitable hydrogenation precursor of pyruvate, lactate or

other metabolically-linked molecules has led Reineri et al.142

to develop the method of side-arm hydrogenation PHIP (PHIPSAH).In PHIP-SAH, parahydrogen is added to an unsaturated

ester of the molecule of choice in the organic phase, where the

hydrogenation reaction is most effcient, then polarization

is transferred from 1H to the [1-13C] atom of the carboxylic

acid of interest, and fnally the ester ³side-arm´ is hydrolytically cleaved to yield the HP carboxylic acid of interest along

with ester alcohol in the aqueous phase. Hyperpolarized

[1-13C]pyruvate, [1-13C]acetate142 and [1-13C]lactate143

have been demonstrated using this approach.

Following optimization of the initial experimental procedure with a view to in vivo application,144 a 13C polarization of a5 on [1-13C]pyruvate at the time of experiment was

obtained, enabling realization of the frst in vivo metabolic

MR spectroscopy and imaging in a mouse model of dilated

cardiomyopathy,145 the results of which are highlighted in

Fig. . Whilst the sensitivity remains relatively low compared with that produced by d-DNP, a recent comparison of

the polarization effciency of several pyruvate and acetate

precursors has provided insights into the best substrate of

choice for future in vivo metabolic MRI applications.14

In particular, hydrogenation products ethyl acetate and allyl

pyruvate (hydrogenation products of vinyl acetate and

propargyl pyruvate, respectively) were found to yield the

highest 13C polarization.14 Furthermore, when a deuterated

Fig. 7 (a) Slice-selective dynamic 13C MRS of a healthy wild-type

mouse after injection of HP

[1-13C]pyruvate produced by

parahydrogen-induced polarization (PHIP)-side-arm hydrogenation (SAH), and (b) corresponding

whole-body 13C chemical shift

imaging (CSI) of [1-13C]pyruvate

and [1-13C]lactate (reproduced

from Figs. 2 and 3 of Cavallari

et al.145 under the Creative

Commons CCBY License).

a

b

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precursor is combined with optimized polarization transfer

techniques, 13C polarization of more than 5 on acetate has

been realized using the vinyl ester precursor,14 which may

permit in vivo investigations of acetyl-CoA synthetase

activity in the near future by PHIP.

Future Perspectives

Ongoing and future clinical trials of [1-13C]pyruvate MRI

serve a critical role in evaluating the clinical viability of the

technique for and beyond oncological studies of metabolism,

and also in assessing the reproducibility and robustness of

hyperpolarized MR acquisition methods and analysis procedures in order to provide guidelines to standardize workÀow

for future multi-site validation studies.5 In particular, robust

clinical comparison studies of HP [1-13C]pyruvate MRI and 1F-FD*-P(T in several oncological pathologies are required

to further understanding of the relationship between the pathophysiological information gleaned from each technique and

further accelerate clinical translation.9,9 Clinical trials of

d-DNP probes such as [1-13C]fumarate, [1-13C]bicarbonate

and others are either pending or expected in the near future,

and co-polarization techniques are likely to yield unprecedented access to multiple aspects of metabolic function with a

single hyperpolarized dose.1,14 d-DNP probe development

has not ceased with the advent of clinical application of [1-13C]

pyruvate, with several novel probes reported in the last few

years.149,151 In parallel to clinical studies, the fundamental

science of d-DNP remains a feld of active development.152

Whilst biomedical applications of PHIP are relatively

few in number to date when compared with those of d-DNP,

novel approaches such as PHIP-SAH offer an expanded palette of polarizable molecular targets and a low-cost means

of generating HP [1-13C]pyruvate for preclinical and with

further refnement, eventually clinical applications.142,145

In addition, the development of increasingly effcient and

versatile hydrogenation catalysts is a thriving research feld

(see e.g. *l|ggler et al.,153 /eutzsch et al.154). In particular,

rhodium-based catalysts commonly used for effcient hydrogenation predominantly yield cis-selective products, but a

novel trans-selective ruthenium-based catalyst has recently

been shown to demonstrate hyperpolarized [1-13C]fumarate

by parahydrogen addition to acetylene[1-13C]dicarboxylate

for the frst time.155 With appropriate fltering of the catalyst15

and other unwanted co-solvents or hydrolysis side products

(in the case of PHIP-SAH), the purity of injected doses can

be improved to appropriately high levels with a view to clinical application in the foreseeable future.

It is not only the 13C nucleus that shows promise for biomedical hyperpolarized MRI applications as previously

noted, the 15N nucleus has a relatively low MR sensitivity, but

exhibits extremely long polarization lifetimes and metabolic

probes can be prepared in an environment suitable for biological application, analogous to 13C.15,15 In addition, 19F, which

has a gyromagnetic ratio and therefore a baseline sensitivity

similar to that of the proton, may fnd biomedical application

in targeted MRI of hyperpolarized 19F-labelled drugs, though

limited progress in this direction has been made to date.159

Furthermore, while all the above noted applications pertain

to liquid-phase molecular probes, parahydrogen can be used

in combination with a solid-phase catalyst to generate

1

H-hyperpolarized propane (from propylene) in the gaseous

phase.1,11 which shows some promise as a relatively cheap

alternative to hyperpolarized noble gases for biomedical lung

imaging, though the high 1H background signal may be

problematic and no in vivo experiments have been attempted

to date.

Finally, the SA%R( parahydrogen method, wherein

polarization transfer occurs by reversible exchange and the

target molecule remains chemically unaltered upon interaction with parahydrogen, has the potential yield heteronuclear

(

13C, 15N) hyperpolarization on a broader range of molecular

imaging probes than conventional PHIP and may lead to several unprecedented avenues of biomedical application.12

Although to date no in vivo experiments have been performed

with SA%R(-polarized probes, the recent demonstration of

both hyperpolarized [1-13C] and [2-13C]pyruvate,14 although

at relatively low polarizations, represents a signifcant step

toward biomedical application.

Acknowledgments

N-S is an international research fellow of the -apanese

Society for the Promotion of Science (-SPS).

Conficts of Interest

The authors declare that they have no conÀicts of interest.

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Hyperpolarized 13C MRI: State of the Art

and Future Directions

综述简介

综述概览

代谢ڦᅴ׉ံྫྫᇀऐ༹ፇኯڦՎࣅLjԨጹຎ߁ຎକג极ڦࣅᇱ૙Ljג极ࣅ 13C ڦ༑ኍ݀ቛLjג极ࣅ 13C ڦଣضമ研

৯ࢅଣض研৯Ljᅜत࿄ઠڦᆌᆩമৠݛࢅၠă

什么是超极化?

ሞଣض๑ᆩڦ༹࿒ࢅׇഽူ MRILj13CాᇸڦࢃMRI႑گ࢔ࡽ ᆯᇀഄཀ඗گ܈ݿDŽৈሀ 1.1% ༐๟ 13CDžࢃگࢅጲ჉极ࣅDŽ

ጲ჉ுᆶںࡻ࢔ᇑྔև磁ׇܔഋDžă 13C ܔൠڦ၎ܔ႑ࡽ 1 (1 H) ๟ 0.016 एᇀ 13C ڦ჉磁Բሀྺ 1 ڦ຺ݴኮᅃ H. 13C

ڦ၎ܔ႑ࡽ 13C گڦཀ඗܈ݿ৊ᅃօইگ 1.1%Lj၎Բኮူ 1 ࡗגڦ 99% H. ߀ ৊13C ڦࢃ MRI ႑ࡽLj༑ኍ੗ׯࢇ ޷集

ᅜሺे13C Քऻڦ౪܈ ᅃዖݴጱLjཚ޷׉集ڟ 13C ڦ 99%ă MRI႑ࡽ੗ᅜཚࡗᅜူײࡗ৊ᅃօ၂ጣሺे ג极ࣅDŽ཮ 1Džă

ג极ڦࣅᇱ૙๟एᇀሞگ࿒ߛࢅ࿒ူ ሞ磁ׇዐLjۉጱਏᆶڦߛ׉ݥ极ࣅೝ຤DŽनबࢭ໯ᆶۉڦጱۼᅜ၎ཞݛڦ๕ಇ

ଚDž ݛၠDžăኄዖߛೝ຤ڦ极ࣅ੗ᅜገᅎڟ 13C Քऻڦ༑ኍLjሺे໲்ڦ MRI ႑ࡽ

HP C13 的临床前研究

ଣضമ研৯ܔᇀג极ࣅ研৯ᆖၚዘۇٴLjዷᄲሞ዗ୀLj႐ე࠶दթLjะሤदթࢅ஥Ⴀᄁኢݛڪ௬৊ႜ研৯ă

硬件及技术上的支持

SpinLab๟एᇀd-DNPፌႎरຍߛڦཚଉ࿮ਪ极ࣅᅏLjփၩࡼᅂ࡜Ljሞ~0.9 Kࢅ5Tူ߾ፕLjࡀ׉इٳߛڥ40%ڦ]1-13C]

եཛྷ໗极ࣅLj๟ങৃྺኹྸᅃԥ಼ጚᆩᇀටૌᆌᆩڦဣཥኟሞ全球੺໏೵तժۇٴଉᆩᇀଣض研৯ዐăᅜत磁共振ฉ

ڦጆᆩڦ໏੺ׯၟႾଚLj૩ස EPSI Ⴞଚă

临床上的超极化研究

ଣضฉਸቛට༹ג极ࣅํᄓዷᄲሞLjമଚ၇ҵLj୕ా዗ୀᅜत႐ሤ代谢ૌदթăኄ૛ኵڥᅃ༵ڦ๟एᇀമଚ၇ҵڦ

研৯ፌྺݘ࠽Lj੗ᅜፔגڟራ೺ೠࢅࠚ৛ጚݴ೺ă

ႎ႙༑ኍڦ研݀ࢅ݀၄LjأକHP [1-13C]եཛྷ໗༑ኍኮྔLj࣏ᆶۇٴଉႎ႙ڦ༑ኍԥ研݀Lj༑໭ᆩᇀփཞթ૙࠵ڦײࡗִă

Ԉઔג极ࣅ] 2-13C] եཛྷ໗DŽෙ᷌໗თ࣍ాዐक़代谢࿿ೠࠚDžLj[1-13C] ౖ໎DŽ࠺ጀೠࠚDžLj[1,4-13C2] ޷க໗DŽဦԇ࣋

ຶೠࠚDžڪڪăᆶၳܠڦዖ༑ኍ共极ࣅᄺ๟࿄ઠݛڦၠࢅํ၄ܠୟ০ॠ֪代谢ݛڦ݆ă

࿄ઠג极ࣅ研৯ݛڦၠLjԨ࿔ኸڼ؜ᅃ࿄ઠධႴᄲሞג极ࣅ磁共振෢௮Ⴞଚዐ৊ႜ研৯Ljઠ༵ื཮ၟዊଉࢅኍܔփ

ཞഗࢅ࠳ፇኯڦ෢௮研৯ăଷᅃݛ௬ג极ࣅरຍᄺႴᄲၠଣض৊ႜገࣅनႴᄲ߸ڦܠଣضઠକ঴޿रຍLj໲੗ᅜټ

ઠթ૙ฯ዁๟एإᅅბڦ代谢研৯

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REVIEWS AND COMMENTARY • REVIEW

Altered metabolism is central to many human diseases, such as cancer, cardiovascular disease, diabetes, and a

variety of inflammatory conditions. !e most commonly

used imaging strategy in the clinic for interrogating metabolism, particularly in cancer, is PET with the glucose

analog 18F fluorodeoxyglucose (FDG). FDG PET provides

information regarding tissue glucose uptake and has been

highly clinically successful. However, it cannot help assess

downstream metabolism, which may be useful in the diagnosis and treatment monitoring of a variety of diseases.

Carbon 13 (13C) MRI is particularly attractive for metabolic imaging because carbon serves as the backbone of

nearly all organic molecules, thus allowing the investigation

of a wide range of biochemical processes that are relevant to

human diseases. However, the low natural abundance of the

13C isotope, at 1.1%, has made in vivo imaging extremely

challenging. !is limitation has been overcome by the recent

development of the dynamic nuclear polarization technique,

which can dramatically, albeit temporarily, increase the signal of 13C-labeled molecules by more than 10000 fold (1).

Hyperpolarized (HP) 13C MRI has emerged as a powerful

molecular imaging strategy that allows safe, nonradioactive,

real-time, and pathway-specific investigation of dynamic

metabolic and physiologic processes that were previously

inaccessible to imaging. In this review, we will provide an

overview of the methods of hyperpolarization and the various biologic processes that can be interrogated by using HP

13C probes, with a focus on HP 13C pyruvate. We will also

summarize the technical and regulatory requirements of human HP 13C studies and highlight the emerging clinical applications of this molecular imaging technology.

Hyperpolarization

At body temperature and field strengths used in clinical

MRI, the MRI signal of 13C endogenous nuclei is very low

because of its low natural abundance (only about 1.1%

of carbon is 13C) and low nuclear spin polarization (the

spins are not well aligned to the external magnetic field).

!e relative signal of 13C to hydrogen 1 (1H) is 0.016

based on the gyromagnetic ratio of 13C being approximately one-fourth of that of 1

H. !e relative signal of 13C

is further reduced by the low natural abundance of 13C of

1.1%, compared with more than 99% for 1H. To improve

the MRI signal of 13C nuclei, probes can be synthetically

enriched to increase the concentration of the 13C label in

a molecule, commonly enriched to 99% of 13C. MRI signal can be further increased dramatically by the process of

hyperpolarization (Fig 1). !e principle of hyperpolarization is based on the fact that at low temperature and high

magnetic field, electrons have a very high level of polarization (ie, nearly all the electrons are aligned in the same

direction). !is high level of polarization can be transferred to 13C-labeled probes, increasing their MRI signals.

!is transfer of polarization is accomplished by mixing

radicals (a source of free electrons) with the 13C-labeled

probe(s) to be hyperpolarized and placing the mixture in

a polarizer at a magnetic field typically of 3.0–5.0 T and

at a low temperature (approximately 1 K). Microwave irradiation is then applied to transfer the polarization from

unpaired electrons in a trityl radical to the 13C-labeled

probes (1). Depending on the molecule to be polarized

and the operating field strength and temperature of the

Hyperpolarized 13C MRI: State of the Art and Future

Directions

Zhen J. Wang, MD • Michael A. Ohliger, MD, PhD • Peder E. Z. Larson, PhD • Jeremy W. Gordon, PhD • Robert

A. Bok, MD, PhD • James Slater, PhD • Javier E. Villanueva-Meyer, MD • Christopher P. Hess, MD, PhD • John

Kurhanewicz, PhD • Daniel B. Vigneron, PhD

From the Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143. Received October 25, 2018; revision

requested November 24; final revision received January 5, 2019; accepted January 9. Address correspondence to Z.J.W. (e-mail: Zhen.Wang@ucsf.edu).

Supported by the National Institute of Biomedical Imaging and Bioengineering (P41EB013598, R01EB016741, R01EB017449), the American Cancer Society

(RSG-18-005-01-CCE), the National Cancer Institute (P01CA118816, R01CA183071), and the National Institute of Diabetes and Digestive and Kidney Diseases

(R01DK097357, R01DK115987).

Conflicts of interest are listed at the end of this article.

Radiology 2019; 291:273–284 • https://doi.org/10.1148/radiol.2019182391 • Content codes:

Hyperpolarized (HP) carbon 13 (13C) MRI is an emerging molecular imaging method that allows rapid, noninvasive, and pathwayspecific investigation of dynamic metabolic and physiologic processes that were previously inaccessible to imaging. !is technique

has enabled real-time in vivo investigations of metabolism that are central to a variety of diseases, including cancer, cardiovascular

disease, and metabolic diseases of the liver and kidney. !is review provides an overview of the methods of hyperpolarization and 13C probes investigated to date in preclinical models of disease. !e article then discusses the progress that has been made in translating this technology for clinical investigation. In particular, the potential roles and emerging clinical applications of HP [1-13C]

pyruvate MRI will be highlighted. !e future directions to enable the adoption of this technology to advance the basic understanding of metabolism, to improve disease diagnosis, and to accelerate treatment assessment are also detailed.

©RSNA, 2019

Online supplemental material is available for this article.

This copy is for personal use only. To order printed copies, contact reprints@rsna.org

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State of the Art and Future Directions of Hyperpolarized Carbon 13 MRI

274 radiology.rsna.org n Radiology: Volume 291: Number 2—May 2019

shift difference between the probe and its metabolites at the

labeled position. Larger differences in chemical shift enable

differentiation between the probe and metabolites more readily and therefore enable more accurate metabolic quantification. Successful HP probes additionally must be water soluble

at physiologic pH values and have cellular uptake that is sufficiently rapid to allow observation of metabolism during the

time frame of the HP study.

"e most widely studied HP probe to date is [1-13C]pyruvate. It polarizes well (up to 50% polarization level in current

clinical polarizers) and has a long T1 (approximately 67 seconds

in solution at 3.0 T), thereby permitting in vivo investigation

with high signal-to-noise ratio. Importantly, [1-13C]pyruvate is

a highly biologically relevant probe, as pyruvate lies at a critical

branch point of multiple metabolic pathways, including glycolysis,

the tricarboxylic acid (TCA) cycle, and amino acid biosynthesis

(Fig 2). On injection into a living system, HP [1-13C]pyruvate is

rapidly taken up into the cells and metabolized within the cytosol into [1-13C]lactate and [1-13C]alanine by the enzymes lactate

dehydrogenase (LDH) and alanine transaminase, respectively.

HP [1-13C]pyruvate is also transported into the mitochondria

and is converted by the enzyme pyruvate dehydrogenase (PDH)

into 13C CO2

and acetyl-coenzyme A, thereby serving as a readout of PDH activity and flux toward the TCA cycle. [1-13C]pyruvate has been used extensively to interrogate metabolism in a

variety of diseases such as cancer, ischemia, and inflammation in

preclinical models (discussed in detail below). Importantly, it has

also been translated for clinical metabolic investigations and has

been shown to be safe and feasible (2).

"ere are numerous other HP 13C probes, mainly composed

of endogenous biomolecules, that have shown great promise

for investigating metabolism relevant to human diseases. Examples include [2-13C]pyruvate for probing mitochondrial

metabolism (3,4), [1,4-13C2]fumarate for assessing tissue necrosis (5–9), 13C bicarbonate for measuring pH (10–13), [1- 13C]dehydroascorbate (DHA) for interrogating redox capacity

(14–18), and 13C urea for imaging perfusion (19–22). While

many of these probes have so far been investigated only in

preclinical disease models, several of them, including [2-13C]

pyruvate, [1,4-13C2]fumarate, and 13C urea are actively being

evaluated for clinical translation.

Abbreviations

DHA = dehydroascorbate, FDG = fluorine 18 fluorodeoxyglucose, HP

= hyperpolarized, kPL = apparent rate constant for pyruvate-to-lactate

conversion, LDH = lactate dehydrogenase, PDH = pyruvate dehydrogenase, TCA = tricarboxylic acid, TRAMP = transgenic adenocarcinoma

of mouse prostate

Summary

Hyperpolarized carbon 13 MRI is an emerging molecular imaging

technique that is actively undergoing clinical translation at multiple

institutions.

Essentials

n Hyperpolarization, achieved by means of dynamic nuclear polarization, dramatically enhances the MRI signal of carbon 13 (13C)

labeled molecules by more than 10 000 fold.

n Hyperpolarized 13C MRI allows in vivo probing of enzyme-mediated metabolic processes relevant to human diseases.

n Work is ongoing in the clinical translation of hyperpolarized 13C

MRI, with numerous emerging applications in oncology, diabetes,

and heart disease, as well as metabolic diseases of the liver and kidney.

polarizer, the hyperpolarization process takes between 30 and

120 minutes. "e frozen HP sample is then rapidly dissolved

by a heated and pressurized bolus of a biologically compatible

buffer solution. "e solution retains a high level of polarization

and can be formulated to be at physiologic pH, osmolarity, and

temperature for in vivo injection and metabolic investigations.

In a 3.0-T field and at room temperature, the 13C thermal equilibrium polarization is approximately 0.00025% aligned with

the external magnetic field; with hyperpolarization, the polarization increases to approximately 30%–40%, an increase of

over 100 000 fold (1), thereby dramatically increasing the MRI

signal. "e enhanced signal, however, is typically available only

for a short period of time (ie, 1–2 minutes), as the polarization

decays back to its thermal equilibrium level at a rate dependent on the spin-lattice relaxation time (T1) of the 13C labeled

nucleus. "erefore, rapid imaging is needed to acquire high

signal-to-noise ratio metabolic data with minimal polarization

loss and to measure fast metabolic processes.

HP 13C Probes

An advantage of HP 13C technology is the diverse array of

probes that can be polarized. "e most commonly studied HP

probes have been endogenous biomolecules modified only by

the 13C enrichment, and they have been applied to interrogate

metabolic and physiologic processes associated with a variety of

neoplastic, inflammatory, and metabolic diseases (Table). "e

selection of the 13C enrichment site should take into account

two important considerations. First, the labeled carbon atom

should have a long longitudinal relaxation time (T1), as the T1

determines how quickly the polarization of the probe decays

back to thermal equilibrium once it is removed from the polarizer. Longer T1 facilitates preservation of the enhanced MRI

signal and therefore more accurate quantification of metabolism in vivo. Carbon atoms that do not have directly attached

protons, such as those in carbonyl groups, usually have longer

T1 relaxation times. Another consideration is the chemical

Figure 1: Processes for increasing MRI signal of carbon 13 (

13C)

nuclei. DNP = dynamic nuclear polarization, NMR = nuclear magnetic

resonance.

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Radiology: Volume 291: Number 2—May 2019 n radiology.rsna.org 275

metabolic reprogramming and has been applied to numerous

models of cancer (23–33). For example, increased HP [1-13C]

pyruvate-to-lactate conversion has been observed in a transgenic adenocarcinoma of mouse prostate (TRAMP) model,

with the level of 13C lactate correlating with tumor histologic

grade (23) (Fig 3). In a Myc oncogene–driven liver cancer

model, increased HP [1-13C]pyruvate conversion to lactate and

alanine was observed to precede tumor formation, and there

was a dramatic reversal of pyruvate-to-lactate conversion during early tumor regression before any size change (24). HP [1-

13C]pyruvate–to-lactate conversion and lactate efflux were able

to help differentiate benign renal tumors from renal cell carcinomas in an ex vivo model of patient-derived renal tumor tissues (26). #ese studies have also demonstrated a mechanistic

link between HP lactate signal and cellular alterations such as

elevated expression of LDH and monocarboxylate transporters (lactate transporters) that are essential to fully understand

cancer metabolism.

HP [1-13C]pyruvate has also been shown to be a useful

probe to monitor early anticancer therapies. Successful therapies are usually associated with a decrease in pyruvate-to-lactate

HP Probes in Preclinical Disease Models

Preclinical studies are critical in testing the feasibility and safety

of new HP probes and in developing and refining the methods for their use in specific diseases. In addition, preclinical

HP investigations have contributed to our understanding of

metabolism and its modification in disease processes and following therapy, thereby yielding important information that is

of clinical value. #ere are more than 50 preclinical polarizers

installed worldwide, facilitating a large number of scientific investigations in a variety of diseases.

Cancer

An increase in aerobic glycolysis and lactate production, also

known as the Warburg effect, is characteristic of many tumors.

Specifically, pyruvate generated from glucose metabolism is

preferentially converted to lactate by LDH rather than entering

the TCA cycle for oxidative metabolism and adenosine triphosphate generation. #is lactate production occurs despite the

presence of adequate tissue oxygenation. Hence, HP [1-13C]

pyruvate is an ideal probe to noninvasively interrogate such

Selected Hyperpolarized Carbon 13 Probes Studied to Date

Probe

Metabolic or Physiologic

Processes Interrogated Applications T1 (sec) Chemical Shift (ppm)

[1-13C]pyruvate Glycolysis; LDH, ALT,

PDH activity

Cancer, ischemia,

inflammation

67 (At 3.0 T) [1-13C]pyruvate: 173; [1-13C]lactate:

185; [1-13C]alanine: 178; [1-13C]

bicarbonate: 162

[2-13C]pyruvate TCA cycle metabolism Cancer, cardiac

metabolism

39 (At 3.0 T) [2-13C]pyruvate: 207.8; [2-13C]lactate:

71; [2-13C]alanine: 53; [5-13C]glutamate: 183.8; [1-13C]acetylcarnitine:

175.2; [1-13C]acetoacetate: 177.3;

[3-13C]acetoacetate: 212.7

[1-13C]bicarbonate pH Cancer, ischemia 50 (At 3.0 T) [1-13C]bicarbonate: 161; [1-13C]CO2

:

125

[1,4-13C2

]fumarate Cellular necrosis Cancer, acute renal

tubular necrosis

24 (At 9.4 T) [1,4-13C2]fumarate: 175.4; [1-13C]

malate: 181.8

[5-13C]glutamine Glutaminase activity,

glutamine transport

Cancer 16 (At 9.4 T) [5-13C]glutamine: 178.5; [5-13C]glutamate: 181.5

[1-13C]dehydroascorbate Redox Cancer, diabetes 57 (At 3.0 T) [1-13C]dehydroascorbate: 174; [1-13C]

vitamin C: 177.8 13C urea Perfusion Cancer, cardiovascular

disease, kidney disease

47 (At 3.0 T) 13C urea: 165

[1-13C]acetate TCA cycle flux, fatty acid

oxidation

Ischemia, cardiac

metabolism

40 (At 9.4 T) [1-13C]acetate: 182.5; [1-13C]AcCoA:

202.1; [1-13C]ALCAR: 174; [5-13C]

citrate: 179.7

[1-13C]alpha-ketoglutarate Mutant IDH expression Cancer 52 (At 3.0 T) [1-13C]alpha-ketoglutarate: 172.6;

[1-13C]2-HG: 183.9

[2-13C]dihydroxyacetone Gluconeogenesis Diabetes 39 (At 3.0 T) [2-13C]dihydroxyacetone: 213.4;

[2–13C]G3P: doublet at 75.0 and

70.4; [2–13C]GA3P: 73.8; [2–13C]

PEP: 151.1

[1,3-13C2

]acetoacetate Redox Cancer, ischemia,

diabetes

58 (At 3.0 T) [1,3-13C2]acetoacetate: 175; [1,3-13C2]

bOHB: 180.4

Note.—AcCoA = acetyl-coenzyme A, ALCAR = acetylcarnitine, ALT = alanine transaminase, bOHB = b-hydroxybutyrate, GA3P =

glyceraldehyde-3-phosphate, G3P = glycerol-3-phosphate, IDH = isocitrate dehydrogenase, LDH = lactate dehydrogenase, PEP = phosphoenolpyruvate, PDH = pyruvate dehydrogenase, TCA = tricarboxylic acid, 2-HG = 2-hydroxyglutarate.

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interest, as an acidic tumor microenvironment is implicated in

tumor aggressiveness, metastatic potential, and therapeutic response (51).

!ese initial studies demonstrate the promise of HP 13C MRI

in advancing our understanding of cancer metabolism and metabolic response to treatment and, importantly, show the potential

of this strategy in detecting early response versus nonresponse,

which is critical for enabling adaptive therapies.

Cardiovascular Disease

Alterations in perfusion and energy metabolism are central to

many cardiovascular diseases, making them a particularly promising application for HP 13C MRI. Perfusion can be mapped

quantitatively by studying the distribution of HP 13C urea (52).

Unlike T1-weighted 1H MRI using gadolinium-based perfusion

agents, the signal arising from HP 13C urea is linearly dependent

on concentration, thus simplifying quantification. Quantitative perfusion mapping with HP 13C urea MRI may be useful

in identifying ischemia in patients with balanced hypoperfusion from three-vessel disease, where qualitative gadoliniumenhanced MRI perfusion assessment may be insufficient (53).

HP MRI with [1-13C]pyruvate can depict acute changes in

myocardial metabolism after ischemia and reperfusion, thereby

potentially enabling in vivo monitoring of the metabolic effects

of reperfusion strategies (54). Additionally, simultaneous polarization and administration of HP 13C urea and [1-13C]pyruvate

permit simultaneous interrogation of cardiac metabolism and

perfusion (22). Because HP 13C MRI acquisitions take only 1–2

minutes, this modality has a speed advantage over methods such

as PET metabolism/perfusion mismatch studies, where the imaging time approaches 30 minutes. !e ability to rapidly assess

metabolism/perfusion mismatch and myocardial viability is of

clinical relevance in guiding revascularization following acute

infarction, in clarifying the functional significance of a perfusion defect, and in guiding treatment selection for patients with

angina in the absence of obstructive coronary artery disease.

HP MRI can also help monitor the flux from [1-13C]pyruvate to bicarbonate through the mitochondrial enzyme PDH as

a way to examine the relative contribution of glucose and fatty

acid oxidation (substrate selection) to energy production in the

heart (55–60). In diabetes, the hyperthyroid heart, and dilated

cardiomyopathy, flux through PDH in the heart is reduced as

measured by HP [1-13C]pyruvate MRI (56–58). In contrast, in

hypertrophic cardiomyopathy from hypertension, flux through

PDH is increased, indicating a preference for glucose metabolism rather than fatty acid oxidation (60). Other studies have

also utilized HP [2-13C]pyruvate MRI to interrogate TCA cycle

metabolism during reperfusion and cardiac remodeling following

myocardial infarction (61,62). !ese data show the potential of

metabolic profiling with HP 13C MRI as a noninvasive tool to

improve understanding of the mechanism of various heart diseases, provide more specific diagnoses, and provide therapeutic

guidance.

Liver Disease

A growing body of literature has indicated a strong potential

for HP 13C MRI in the diagnosis and monitoring of liver injury

conversion, mediated by different mechanisms from various

treatments (34–45). For example, in a model of glioblastoma,

decreased lactate production was observed with early treatment

response to everolimus (a mammalian target of rapamycin, or

mTOR, inhibitor) before any tumor size change and was associated with a decrease in the LDH enzyme that mediates the pyruvate-to-lactate conversion (37). Treatment with temozolomide

(a DNA damaging drug) in a glioblastoma model also resulted in

lower lactate production but was related to a decrease in pyruvate

kinase PKM2, a glycolytic enzyme that indirectly controls pyruvate metabolism (39). Interestingly, in an ovarian cancer model,

treatment with a tyrosine kinase inhibitor (pazopanib) led to significantly higher HP pyruvate-to-lactate conversion at 2 days after

treatment initiation, while no change was observed at FDG PET

(40). !e increased pyruvate-to-lactate conversion was hypothesized to reflect increased hypoxia with elevated lactate production as a result of the antiangiogenic effects of the drug (40).

In addition to [1-13C]pyruvate, multiple other probes have

been used to study cancer metabolism preclinically. For example,

increased HP [1,4-13C2]fumarate–to-malate conversion was seen

early following cancer therapy prior to significant changes in tumor size in models of lymphoma (5), breast cancer (46), liver

cancer (47), and colon cancer (48), consistent with increased tumor necrosis. Hence, HP fumarate may be useful in providing

another measure of early treatment response. HP 13C urea has

been used in combination with HP [1-13C]pyruvate to investigate metabolism/perfusion mismatch in a prostate cancer model,

and such mismatch was associated with more aggressive tumors

(21). A recent study (49) also utilized a combination of [1-13C]

pyruvate and HP 13C urea to monitor metabolic and perfusion

changes following high-intensity focused ultrasound treatment

in a TRAMP model. HP 13C bicarbonate has shown promise

for in vivo pH mapping of tumors (10–13,50), which is of great

Figure 2: Schematic of the metabolic pathways of pyruvate. [1-13C]

pyruvate is rapidly taken up into the cells and metabolized within the

cytosol into [1-13C]lactate and [1-13C]alanine by the enzymes lactate

dehydrogenase (LDH) and alanine transaminase (ALT), respectively. Hyperpolarized [1-13C]pyruvate is also transported into the mitochondria

and is converted by the enzyme pyruvate dehydrogenase (PDH) into 13C

CO2 and acetyl Co-A, with CO2 in rapid equilibrium with 13C bicarbonate. TCA = tricarboxylic acid. Red circle = position of 13C labeling.

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