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<2nM) and high selectivity for σ1versus σ2and VAChT (>100-fold). The minus enantiomer, (-)-14a ((-)-TZ3108) (Ki-σ1=1.8±0.4nM, Ki-σ2=6960±810nM, Ki-VAChT=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 (-)-[18F]TZ3108 reached 1.285±0.062 at 5min and 0.802±0.129 at 120min. 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.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States.
authors.forename: Xuyi
authors.initials: X
authors.lastname: Yue
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Jin
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States.
authors.forename: Zonghua
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, United States.
authors.forename: Ethan D
authors.initials: ED
authors.lastname: McSpadden
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, MO, United States.
authors.forename: Linlin
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, MO, United States.
authors.forename: Hubert P
authors.initials: HP
authors.lastname: Flores
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States; Department of Neurology, Washington University School of Medicine, St Louis, MO, United States.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, United States.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Parsons
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States. Electronic address: tuz@mir.wustl.edu.
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008252:Macaca fascicularis; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D050494:Vesicular Acetylcholine Transport Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D008024:Ligands; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D050494:Vesicular Acetylcholine Transport Proteins
keywords: Enantiomer; Fluorine-18; PET imaging; σ(1) receptor