Issue 24, 2017

Synthesis, resolution, and in vitro evaluation of three vesicular acetylcholine transporter ligands and evaluation of the lead fluorine-18 radioligand in a nonhuman primate

Abstract

The vesicular acetylcholine transporter (VAChT) is a reliable biomarker for assessing cholinergic dysfunction associated with dementia. We recently reported three new potent and selective carbon-11 labeled VAChT radiotracers. Herein, we report the resolution with a Chiralcel OD column of three additional fluorine containing VAChT ligands in which a fluoroethoxy or fluoroethylamino moiety was substituted for the methoxy group. An in vitro competitive binding assay showed that (−)-7 had high potency for VAChT (Ki-VAChT = 0.31 ± 0.03 nM) and excellent selectivity for VAChT versus σ receptors (Ki-σ1 = 1870 ± 250 nM, Ki-σ2 = 5480 ± 140 nM). Three different radiolabeling approaches were explored; the radiosynthesis of (−)-[18F]7 was successfully accomplished via a stepwise two-pot, three-step method with moderate yield (11 ± 2%) and high radiochemical purity (>98%). PET imaging studies in a nonhuman primate indicated that (−)-[18F]7 rapidly entered the brain and accumulated in the VAChT-enriched striatum. The uptake of (−)-[18F]7 in the target striatal area peaked at 10 min and displayed improved clearance kinetics compared to the VAChT tracer [18F]VAT, which has been approved by the Food and Drug Administration (FDA) for first-in-man studies. These studies justify further investigation of (−)-[18F]7 and exploration of the structure–activity relationships of these fluoroethoxy and fluoroethylamino analogs.

Graphical abstract: Synthesis, resolution, and in vitro evaluation of three vesicular acetylcholine transporter ligands and evaluation of the lead fluorine-18 radioligand in a nonhuman primate

Supplementary files

Article information

Article type
Paper
Submitted
05 Apr 2017
Accepted
30 May 2017
First published
30 May 2017

Org. Biomol. Chem., 2017,15, 5197-5209

Synthesis, resolution, and in vitro evaluation of three vesicular acetylcholine transporter ligands and evaluation of the lead fluorine-18 radioligand in a nonhuman primate

X. Yue, H. Jin, H. Liu, Z. Luo, X. Zhang, K. Kaneshige, H. P. Flores, J. S. Perlmutter, S. M. Parsons and Z. Tu, Org. Biomol. Chem., 2017, 15, 5197 DOI: 10.1039/C7OB00854F

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