Synthesis, resolution, and in vitro evaluation of three vesicular acetylcholine transporter ligands and evaluation of the lead fluorine-18 radioligand in a nonhuman primate. Issue 24 (7th June 2017)

• Record Type: Journal Article
• Authors: Yue, Xuyi; Jin, Hongjun; Liu, Hui; Luo, Zonghua; Zhang, Xiang; Kaneshige, Kota; Flores, Hubert P.; Perlmutter, Joel S.; Parsons, Stanley M.; Tu, Zhude
• Is Part Of: Organic & biomolecular chemistry. Volume 15:Issue 24(2017)
• Page Start: 5197
• Page End: 5209
• Publication Date: 2017-06-07
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c7ob00854f
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Three F-18 radiolabeling methods were explored for a potent VAChT tracer and the tracer was further evaluated in a nonhuman primate by PET. 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 ( K i-VAChT = 0.31 ± 0.03 nM) and excellent selectivity for VAChT versus σ receptors ( K i-σ1 = 1870 ± 250 nM, K i-σ2 = 5480 ± 140 nM). Three different radiolabeling approaches were explored; the radiosynthesis of (−)-[ 18 F]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 (−)-[ 18 F]7 rapidly entered the brain and accumulated in the VAChT-enriched striatum. The uptake of (−)-[ 18 F]7 in the target striatal area peaked at 10 min and displayed improved clearance kinetics compared to the VAChT tracer [ 18 F]VAT, which has been approved by the Food and Drug Administration (FDA) for first-in-man studies. These studies justify further investigation of (−)-[ 18 F]7 and exploration of the structure–activity relationships of these fluoroethoxy and fluoroethylamino analogs.