@article{4bc3f0a2ad17425688af93351978de76,
title = "Chiral resolution of serial potent and selective σ1ligands and biological evaluation of (−)-[18F]TZ3108 in rodent and the nonhuman primate brain",
abstract = "Twelve optically pure enantiomers were obtained using either crystallization or chiral high performance liquid chromatography (HPLC) separation methodologies to resolve six racemic sigma-1 (σ1) receptor ligands. The in vitro binding affinities of each enantiomer for σ1, σ2receptors and vesicular acetylcholine transporter (VAChT) were determined. Out of the 12 optically pure enantiomers, five displayed very high affinities for σ1(Ki < 2 nM) and high selectivity for σ1versus σ2and VAChT (>100-fold). The minus enantiomer, (−)-14a ((−)-TZ3108) (Ki- σ 1 = 1.8 ± 0.4 nM, Ki- σ 2 = 6960 ± 810 nM, Ki-VAChT = 980 ± 87 nM), was chosen for radiolabeling and further in vivo evaluation in rodents and nonhuman primates (NHPs). A biodistribution study in Sprague Dawley rats showed brain uptake (%ID/gram) of (−)-[18F]TZ3108 reached 1.285 ± 0.062 at 5 min and 0.802 ± 0.129 at 120 min. NHP microPET imaging studies revealed higher brain uptake of (−)-[18F]TZ3108 and more favorable pharmacokinetics compared to its racemic counterpart. Pretreatment of the animal using two structurally different σ1ligands significantly decreased accumulation of (−)-[18F]TZ3108 in the brain. Together, our in vivo evaluation results suggest that (−)-[18F]TZ3108 is a promising positron emission tomography (PET) tracer for quantifying σ1receptor in the brain.",
keywords = "Enantiomer, Fluorine-18, PET imaging, σreceptor",
author = "Xuyi Yue and Hongjun Jin and Zonghua Luo and Hui Liu and Xiang Zhang and McSpadden, {Ethan D.} and Linlin Tian and Flores, {Hubert P.} and Perlmutter, {Joel S.} and Parsons, {Stanley M.} and Zhude Tu",
note = "Funding Information: This work was financially supported by the USA the National Institutes of Health (NIH) through the National Institute of Neurological Disorders and Stroke (NINDS, NS075527), and the National Institute of Mental Health (NIMH, No. MH092797). During the process of accomplishing this work, it also used The Biomedical Mass Spectrometry Resource at Washington University in St. Louis, MO, supported by NIH through the National Institute of General Medical Sciences (NIGMS# 8P41GM103422). The authors thank Robert Dennett in the Cyclotron Facility for 18F radioisotope production. Optical rotation was determined in the laboratory of Dr. Douglas F. Covey in the Department of Molecular Biology and Pharmacology of Washington University. The authors thank John Hood, Williams Emily and Darryl Craig for their assistance with the NHP microPET studies. We thank the Department of Chemistry staff and the Washington University High Resolution NMR Facility for assistance with NMR spectra; purchase of the 400 MHz NMR instrument was partially supported by Grant S10 RR027207 from the NIH Shared Instrument Grant program. The authors would like to thank Ms. Lynne Jones for her proofreading of the manuscript. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",
year = "2017",
doi = "10.1016/j.bmc.2017.01.017",
language = "English",
volume = "25",
pages = "1533--1542",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
number = "4",
}