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Syntheses and Radiosyntheses of Two Carbon-11 Labeled Potent and Selective Radioligands for Imaging Vesicular Acetylcholine Transporter

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Abstract

Purpose

The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. The syntheses and C-11 labeling of two potent enantiopure VAChT inhibitors are reported here.

Procedures

Two VAChT inhibitors, (±)-2 and (±)-6, were successfully synthesized. A chiral HPLC column was used to resolve the enantiomers from each corresponding racemic mixture for in vitro characterization. The radiosyntheses of (−)-[11C]2 and (−)-[11C]6 from the corresponding desmethyl phenol precursor was accomplished using [11C]methyl iodide or [11C]methyl triflate, respectively.

Results

The synthesis of (−)-[11C]2 was accomplished with 40–50 % radiochemical yield (decay-corrected), SA > 480 GBq/μmol (EOB), and radiochemical purity >99 %. Synthesis of (−)-[11C]6 was accomplished with 5–10 % yield, SA > 140 GBq/μmol (EOB), and radiochemical purity >97 %. The radiosynthesis and dose formulation of each tracer was completed in 55–60 min.

Conclusions

Two potent enantiopure VAChT ligands were synthesized and 11C-labeled with good radiochemical yield and specific activity.

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Scheme 1
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Scheme 4

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Abbreviations

ACh:

Acetylcholine

Anal:

Analysis

BBB:

Brain–blood barrier

BOC:

t-butoxycarbonyl

BOPCl:

Bis(2-oxo-3-oxazolidinyl)-phosphinic chloride

Bq:

Becquerel

Calcd.:

Calculated

m-CPBA:

m-chloroperoxybenzoic acid

DMF:

N,N-dimethylformamide

DMSO:

Dimethylsulfoxide

EOB:

End of bombardment

EOS:

End of synthesis

HPL, C:

High-performance liquid chromatography

IBVM, :

5-Iodobenzovesamicol

PET:

, Positron emission tomography

rt:

Room temperature

SA:

Specific activity

SPECT:

Single-photon emission computed tomography

TLC:

Thin layer chromatography

TMS:

Tetramethylsilane

TFA:

Trifluoroacetic acid

UV:

Ultraviolet

VAChT:

Vesicular acetylcholine transporter

Vesamicol:

Trans-2-(4-phenylpiperidino)cyclohexanol

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Acknowledgments

This work was supported by NIH grants NS061025, NS075527, and MH092797. The authors thank William H. Margenau and David Ficke in the Cyclotron Facility for radionuclide production. Optical rotation was determined in the laboratory of Dr. Douglas F. Covey in the Department of Molecular Biology and Pharmacology of Washington University.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd, St. Louis, MO, 63110, USA

    Prashanth K. Padakanti, Xiang Zhang, Junfeng Li, Joel S. Perlmutter & Zhude Tu

  2. Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA

    Stanley M. Parsons

  3. Department of Neurology, Washington University School of Medicine, 510 South Kingshighway Blvd, St. Louis, MO, 63110, USA

    Joel S. Perlmutter

Authors
  1. Prashanth K. Padakanti
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  2. Xiang Zhang
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  3. Junfeng Li
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  4. Stanley M. Parsons
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  5. Joel S. Perlmutter
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  6. Zhude Tu
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Correspondence to Zhude Tu.

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Padakanti, P.K., Zhang, X., Li, J. et al. Syntheses and Radiosyntheses of Two Carbon-11 Labeled Potent and Selective Radioligands for Imaging Vesicular Acetylcholine Transporter. Mol Imaging Biol 16, 765–772 (2014). https://doi.org/10.1007/s11307-014-0748-x

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  • DOI: https://doi.org/10.1007/s11307-014-0748-x

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