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

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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

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Publication details

The article was received on 05 Apr 2017, accepted on 30 May 2017 and first published on 30 May 2017


Article type: Paper
DOI: 10.1039/C7OB00854F
Citation: Org. Biomol. Chem., 2017,15, 5197-5209
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    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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