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In Vitro and In Vivo Characterization of Two C-11-Labeled PET Tracers for Vesicular Acetylcholine Transporter

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Abstract

Purpose

The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. Herein, two potent and selective 11C-labeled VAChT inhibitors were evaluated in rodents and nonhuman primates for imaging VAChT in vivo.

Procedures

For both (−)-[11C]2 and (−)-[11C]6, biodistribution, autoradiography, and metabolism studies were performed in male Sprague Dawley rats. Positron emission tomography (PET) brain studies with (−)-[11C]2 were performed in adult male cynomolgus macaques; 2 h dynamic data was acquired, and the regions of interest were drawn by co-registration of the PET images with the MRI.

Results

The resolved enantiomers (−)-2 and (−)-6 were very potent and selective for VAChT in vitro (K i  < 5 nM for VAChT with >35-fold selectivity for VAChT vs. σ receptors); both radioligands, (−)-[11C]2 and (−)-[11C]6, demonstrated high accumulation in the VAChT-enriched striatum of rats. (−)-[11C]2 had a higher striatum to cerebellum ratio of 2.4-fold at 60 min; at 30 min, striatal uptake reached 0.550 ± 0.086 %ID/g. Uptake was also specific and selective; following pretreatment with (±)-2, striatal uptake of (−)-[11C]2 in rats at 30 min decreased by 50 %, while pretreatment with a potent sigma ligand had no significant effect on striatal uptake in rats. In addition, (−)-[11C]2 displayed favorable in vivo stability in rat blood and brain. PET studies of (−)-[11C]2 in nonhuman primates indicate that it readily crosses the blood-brain barrier (BBB) and provides clear visualization of the striatum; striatal uptake reaches the maximum at 60 min, at which time the target to nontarget ratio reached ~2-fold.

Conclusions

The radioligand (−)-[11C]2 has high potential to be a suitable PET radioligand for imaging VAChT in the brain of living subjects.

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Acknowledgments

This work was supported by NIH grants NS061025, NS075527, and MH092797. The authors thank John Hood, Christina Zukas, and Darryl Craig for their assistance with the nonhuman primate microPET studies.

Conflict of Interest

The authors declare that they have no conflict of interest.

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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, Hongjun Jin, Jinquan Cui, Ruike Wang, Junfeng Li, Joel S. Perlmutter & Zhude Tu

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

    Hubert P. Flores & Joel S. Perlmutter

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

    Stanley M. Parsons

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  1. Prashanth K. Padakanti
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  10. Zhude Tu
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Correspondence to Zhude Tu.

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Padakanti, P.K., Zhang, X., Jin, H. et al. In Vitro and In Vivo Characterization of Two C-11-Labeled PET Tracers for Vesicular Acetylcholine Transporter. Mol Imaging Biol 16, 773–780 (2014). https://doi.org/10.1007/s11307-014-0749-9

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  • DOI: https://doi.org/10.1007/s11307-014-0749-9

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