Chiral resolution of serial potent and selective σ 1 ligands and biological evaluation of (-)-[ 18 F]TZ3108 in rodent and the nonhuman primate brain

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 4; p. 1533
• Main 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
• Format: Journal Article
• Language: English
• Published: England 15.02.2017
• Subjects: Animals; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Dose-Response Relationship, Drug; Ligands; Macaca fascicularis; Molecular Structure; Positron-Emission Tomography; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, sigma - analysis; Receptors, sigma - antagonists & inhibitors; Receptors, sigma - metabolism; Structure-Activity Relationship; Tissue Distribution; Vesicular Acetylcholine Transport Proteins - analysis; Vesicular Acetylcholine Transport Proteins - antagonists & inhibitors; Vesicular Acetylcholine Transport Proteins - metabolism; PET imaging; Enantiomer; σ receptor; Fluorine-18
• ISSN: 1464-3391

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 ) receptor ligands. The in vitro binding affinities of each enantiomer for σ , σ receptors and vesicular acetylcholine transporter (VAChT) were determined. Out of the 12 optically pure enantiomers, five displayed very high affinities for σ (K <2nM) and high selectivity for σ versus σ and VAChT (>100-fold). The minus enantiomer, (-)-14a ((-)-TZ3108) (K =1.8±0.4nM, K =6960±810nM, K =980±87nM), 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 (-)-[ F]TZ3108 reached 1.285±0.062 at 5min and 0.802±0.129 at 120min. NHP microPET imaging studies revealed higher brain uptake of (-)-[ F]TZ3108 and more favorable pharmacokinetics compared to its racemic counterpart. Pretreatment of the animal using two structurally different σ ligands significantly decreased accumulation of (-)-[ F]TZ3108 in the brain. Together, our in vivo evaluation results suggest that (-)-[ F]TZ3108 is a promising positron emission tomography (PET) tracer for quantifying σ receptor in the brain.