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Direct one-step labeling of cysteine residues on peptides with [11C]methyl triflate for the synthesis of PET radiopharmaceuticals

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Abstract

Radiolabeled peptides have emerged as an attractive platform for the diagnostic and therapeutic oncology. However, the 11C-radiolabeling of peptides for positron emission tomography (PET) has been poorly explored, owing to the relatively short half-life of carbon-11 (t 1/2 = 20.3 min) and time-consuming multi-step radiochemical reactions. Existing methods have found limited use and are not routinely encountered in the production of radiotracers. Herein, we propose a facile one-step direct 11C-methylation of cysteine residues in peptides using [11C]methyl triflate under ambient temperatures (20 °C) and short reaction times, on the order of seconds. Good regioselectivity of this method was demonstrated by HPLC in a simple peptide (glutathione, GSH) and a more complex test decapeptide (Trp-Tyr-Trp-Ser-Arg-Cys-Lys-Trp-Thr-Gly) bearing multiple nucleophilic sites. In addition, we extend this method towards the synthesis of [11C]Cys(Me)-[Tyr3-octreotate] as a demonstration of applicability for peptides of biological interest. This octreotate derivative was obtained in non-decay-corrected radiochemical yields of 11 ± 2 % (n = 3) with a synthesis time of approx. 30 min.

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Abbreviations

PET:

Positron emission tomography

GSH:

Glutathione

SPPS:

Solid-phase peptide synthesis

SST:

Somatostatin

SPECT:

Single-photon emission computed tomography

[11C]MB-CHO:

p-[11C]methyoxybenzaldehyde

HPLC:

High-performance liquid chromatography

[11C]MeOTf:

[11C]methyl trifluoromethylsulfonate; [11C]methyl triflate

Gly-Sar:

Glycylsarcosine

DMS:

Dimethyl sulfate

MMS:

Methyl methanesulfonate

CNSC:

Canadian Nuclear Safety Commission

Fmoc:

Fluorenylmethyloxycarbonyl

HBTU:

O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

DIPEA:

N,N-diisopropylethylamine

DMF:

N,N-dimethylformamide

TFA:

Trifluoroacetate; trifluoroacetic acid

TIPS:

Triisopropylsilane

HRMS:

High-resolution mass spectrometry

MALDI-TOF:

Matrix-assisted laser desorption/ionization/time-of-flight

DMSO:

Dimethyl sulfoxide

GSMe:

S-methylglutathione

RP-HPLC:

Reversed-phase high-performance liquid chromatography

MEK:

Methyl ethyl ketone

MeCN:

Acetonitrile

ndc:

Non-decay-corrected

RCY:

Radiochemical yield

EtOH:

Ethanol

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Acknowledgments

This work was financially supported by Canada Foundation for Innovation (CFI) project no. 203639 to R.S.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada

    Joshua Chin, Matthew Vesnaver, Vadim Bernard-Gauthier, Erin Saucke-Lacelle & Ralf Schirrmacher

  2. Department of Chemistry, McGill University, Montreal, Canada

    Joshua Chin

  3. Department of Chemistry, Université de Montréal, Montreal, Canada

    Vadim Bernard-Gauthier

  4. Molecular Imaging and Radiopharmaceutical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany

    Björn Wängler

  5. Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany

    Carmen Wängler

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  1. Joshua Chin
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  2. Matthew Vesnaver
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  3. Vadim Bernard-Gauthier
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  4. Erin Saucke-Lacelle
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Correspondence to Ralf Schirrmacher.

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Chin, J., Vesnaver, M., Bernard-Gauthier, V. et al. Direct one-step labeling of cysteine residues on peptides with [11C]methyl triflate for the synthesis of PET radiopharmaceuticals. Amino Acids 45, 1097–1108 (2013). https://doi.org/10.1007/s00726-013-1562-5

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