Chiral resolution of serial potent and selective σ1 ligands and biological evaluation of (−)-[18F]TZ3108 in rodent and the nonhuman primate brain. Issue 4 (15th February 2017)

• Record Type: Journal Article
• Authors: Yue, Xuyi; Jin, Hongjun; Luo, Zonghua; Liu, Hui; Zhang, Xiang; McSpadden, Ethan D.; Tian, Linlin; Flores, Hubert P.; Perlmutter, Joel S.; Parsons, Stanley M.; Tu, Zhude
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 4(2017)
• Page Start: 1533
• Page End: 1542
• Publication Date: 2017-02-15
• Subjects: calcd calculated -- CH2Cl2 dichloromethane -- CNS central nervous system -- DMSO dimethyl sulfoxide -- [3H]DTG [3H]ditolylguanidine -- DTTA di-p-toluoyl tartaric acid -- EBP emopamil binding protein -- ee enantiomeric excess -- EOB end of bombardment -- EtOH ethanol -- [18F]FTC146 18F-6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one -- HPLC high performance liquid chromatography -- HRMS high resolution mass spectrometry -- IC50 half maximum inhibitory constant -- K2CO3 potassium carbonate -- MeOH methanol -- MP melting point -- MRI magnetic resonance imaging -- NaOH sodium hydroxide -- Na2SO4 sodium sulfate -- NHPs nonhuman primates -- PDE01A phosphodiesterase 10A -- PET positron emission tomography -- p.i. post-injection -- QC quality control -- ROIs Regions of interest -- [11C]SA4503 1-(4-methoxy-3-(methoxy-11C)phenethyl-11C)-4-(3-phenylpropyl)piperazine -- SD Sprague Dawley -- SUV standardized uptake value -- VAChT vesicular acetylcholine transporter -- VOI volume of interest -- Yun122 N-(4-benzylcyclohexyl)-2-(2-fluorophenyl)acetamide; Fluorine-18 -- Enantiomer -- σ1 receptor -- PET imaging; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.01.017
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 ( σ 1 ) receptor ligands. The in vitro binding affinities of each enantiomer for σ 1, σ 2 receptors and vesicular acetylcholine transporter (VAChT) were determined. Out of the 12 optically pure enantiomers, five displayed very high affinities for σ 1 (Ki < 2 nM) and high selectivity for σ 1 versus σ 2 and 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 (−)-[ 18 F]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 (−)-[ 18 F]TZ3108 and more favorable pharmacokinetics compared to its racemic counterpart. Pretreatment of the animal using two structurally different σ 1 ligands significantly decreased accumulation of (−)-[ 18 F]TZ3108 in the brain. Together, our in vivo evaluation results suggest that (−)-[ 18 F]TZ3108 is a promising positron emission tomography (PET) tracer for quantifying σ 1 receptor in the brain.