Therapeutic Target Metabolism Observed Using Hyperpolarized <sup>15</sup>N Choline

Gabellieri, Cristina; Reynolds, Steven; Lavie, A.; Payne, Geoffrey S.; Leach, Martin O.; Eykyn, Thomas R.

doi:10.1021/ja8001293

Cited by 120 publications

(204 citation statements)

References 13 publications

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“…The maximum solid-state polarization was measured to be 3.3 AE 0.3%. This value, which was confirmed by the comparison between the liquid-state thermal equilibrium signal intensity and the hyperpolarized signal measured immediately after dissolution, corresponds to a signal enhancement of 10 000 AE 900 if compared to the room-temperature thermal equilibrium signal in a field of 9.4 T. Nearly the same enhancement factor was reported by Gabellieri et al 41 at 9.4 T, using a commercial DNP polarizer working at 3.35 T and 1.4 K with trityl radicals as polarizing agent.…”

Section: Resultssupporting

confidence: 85%

“…40,41 In vivo relaxation times showed a decrease compared with the in vitro values, which can be explained by the fact that the relaxation times of metabolite are likely to be influenced by the microenvironment. 43 In addition, the in vivo relaxation times exhibited a deviation from the standard mono-exponential decay, with a very fast decay (6 AE 1.5 s) during the first seconds, followed by a slower decay afterwards (126 AE 15 s).…”

Section: This Journal Is C the Owner Societies 2010mentioning

confidence: 98%

“…38 To date, besides optically polarized 3 He and 129 Xe, 39 6 Li is the only hyperpolarized nucleus besides 13 C that has been reported to be detected in vivo. 38 Two recent studies reported remarkably long in vitro longitudinal relaxation times for 15 N Cho, 40,41 suggesting that hyperpolarized 15 N Cho could be a suitable candidate for in vivo experiments.…”

Section: Introductionmentioning

confidence: 99%

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Feasibility of in vivo15N MRS detection of hyperpolarized 15N labeled choline in rats

Cudalbu

Comment

Kurdzesau

et al. 2010

Phys. Chem. Chem. Phys.

102

125

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The increase of total choline in tumors has become an important biomarker in cancer diagnosis. Choline and choline metabolites can be measured in vivo and in vitro using multinuclear MRS. Recent in vivo 13 C MRS studies using labeled substrates enhanced via dynamic nuclear polarization demonstrated the tremendous potential of hyperpolarization for real-time metabolic studies. The present study demonstrates the feasibility of detecting hyperpolarized 15 N labeled choline in vivo in a rat head at 9.4 T. We furthermore report the in vitro (172 AE 16 s) and in vivo (126 AE 15 s) longitudinal relaxation times. We conclude that with appropriate infusion protocols it is feasible to detect hyperpolarized 15 N labeled choline in live animals.

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Section: Resultssupporting

confidence: 85%

Section: This Journal Is C the Owner Societies 2010mentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Feasibility of in vivo15N MRS detection of hyperpolarized 15N labeled choline in rats

Cudalbu

Comment

Kurdzesau

et al. 2010

Phys. Chem. Chem. Phys.

102

125

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“…The enhancement factor was 13 400 compared to a thermal-equilibrium spectrum obtained with 140 scans, 90°pulses, and a repetition time of 1000 s (not shown). Nearly the same enhancement factor was reported by Gabellieri et al 3 at 9.4 T, using a commercial DNP polarizer working at 3.35 T and 1.4 K with trityl radicals as the polarizing agent. The thermal-equilibrium (Boltzmann) polarization can be estimated to be P( 15 N) ) tanh(hν 0 /(2k B T)) ) 2.45 × 10 -6 at T ) 298 K and B 0 ) 7 T. The enhanced polarization P( 15 N) was thus 3.3%, which is consistent with the polarization level measured in the 6 M solid sample prior to dissolution.…”

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confidence: 85%

Proton NMR of ¹⁵N-Choline Metabolites Enhanced by Dynamic Nuclear Polarization

et al. 2009

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Dynamic Nuclear Polarization (DNP) by the so-called 'dissolution' procedure 1 is rapidly gaining momentum as a novel method to enhance weak nuclear magnetic resonance (NMR) signals from molecular tracers, so that one can visualize their biodistribution and metabolism in ViVo. 2 The major limitation of the technique arises from the short lifetimes of hyperpolarized spin states in liquids. In particular, longitudinal relaxation times T 1 of protons in solutions of biomolecules are too short to allow for transport and in ViVo injection of hyperpolarized compounds. Most applications of the technique have therefore focused on 13 C NMR of 13 C-enriched tracers containing nonprotonated carbons with T 1 ( 13 C) ≈ 20-40 s. Choline (CH 3 ) 3 N + CH 2 CH 2 OH plays a key role in several critical biological processes, in particular in the synthesis and metabolism of phospholipids in cell membranes, and in cholinergic neurotransmission. Although the choline molecule does not contain any slowly relaxing carbons, it possesses a quaternary nitrogen with T 1 ( 15 N) > 120 s, which lends itself to hyperpolarization. 3 The conversion of choline to phosphocholine catalyzed by choline kinase has recently been monitored by 15 N NMR in Vitro, 3 employing hyperpolarization of 15 N spins. In ViVo measurements using this method may, however, be hampered by insufficient 15 N peak separation of choline metabolites (∼ 0.2 ppm for phosphocholine vs choline, i.e., only 6 Hz in a field B 0 ) 7 T) and by poor sensitivity of 15 N NMR. A sensitivity improvement by at least an order of magnitude would be required, e.g., to monitor phosphocholine accumulation in tumor cell cultures. 4 The above limitations may be overcome by transferring the hyperpolarization from 15 N to protons, as in recent heteronuclear 2D DNP-NMR experiments. 5 A similar concept was recently used for 13 C enhanced by PASADENA. 6 In this work, we show that one can transfer the long-lived 15 N hyperpolarization to remote methylene CH 2 O protons in choline across three bonds via 3 J( 15 N, 1 H), which significantly improves both the sensitivity and the spectral dispersion of choline metabolites. We also show that T 1 ( 15 N) in choline can be considerably increased by deuteration of the methyl groups.The conventional 1 H spectrum of 15 N-enriched choline is shown in Figure 1A. The peak at 3.19 ppm, which stems from the nine magnetically equivalent methyl protons, is commonly used for in ViVo quantification of choline-containing compounds, 7 whereas the multiplets due to the NCH 2 (3.50 ppm) and CH 2 O protons (4.05 ppm) 8 exhibit an AA′XX′ pattern. 9 The CH 2 O and methyl peaks have additional doublet structures due to 3 J( 15 N, 1 H) ≈ 3.7 Hz and 2 J( 15 N, 1 H) ≈ 0.8 Hz. (In nonenriched choline, one observes triplets due to 3 J( 14 N, 1 H) ) 2.7 Hz and 2 J( 14 N, 1 H) ) 0.6 Hz. 8,9 ) As shown in Figure 1B, the small n J( 15 N, 1 H) couplings in choline can be used to transfer hyperpolarization from 15 N to CH 2 O and methyl protons, using a reversed INEPT pulse sequence. 10,11...

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“…For example, the increase in 13 C label exchange from 13 C-pyruvate to 13 C-lactate, reflective of increased glycolysis, has been validated in many pre-clinical models and more recently in prostate cancer in patients as part of a first-inhuman trial of this technology. Additional cancer-related metabolic processes that have been investigated using DNP combined with MRS include ChoK and glutaminase enzyme activities 16,86,87 as outlined in Figure 2.…”

Section: Implications Of Therapy-induced Physiological Changesmentioning

confidence: 99%

Exploiting tumor metabolism for non-invasive imaging of the therapeutic activity of molecularly targeted anticancer agents

Beloueche‐Babari

Workman²,

Leach³

2011

Cell Cycle

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Therapeutic Target Metabolism Observed Using Hyperpolarized ¹⁵N Choline

Cited by 120 publications

References 13 publications

Feasibility of in vivo15N MRS detection of hyperpolarized 15N labeled choline in rats

Feasibility of in vivo15N MRS detection of hyperpolarized 15N labeled choline in rats

Proton NMR of ¹⁵N-Choline Metabolites Enhanced by Dynamic Nuclear Polarization

Exploiting tumor metabolism for non-invasive imaging of the therapeutic activity of molecularly targeted anticancer agents

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Therapeutic Target Metabolism Observed Using Hyperpolarized 15N Choline

Cited by 120 publications

References 13 publications

Feasibility of in vivo15N MRS detection of hyperpolarized 15N labeled choline in rats

Feasibility of in vivo15N MRS detection of hyperpolarized 15N labeled choline in rats

Proton NMR of 15N-Choline Metabolites Enhanced by Dynamic Nuclear Polarization

Exploiting tumor metabolism for non-invasive imaging of the therapeutic activity of molecularly targeted anticancer agents

Contact Info

Product

Resources

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Therapeutic Target Metabolism Observed Using Hyperpolarized ¹⁵N Choline

Proton NMR of ¹⁵N-Choline Metabolites Enhanced by Dynamic Nuclear Polarization