New Positron Emission Tomography (PET) Radioligand for Imaging σ‑1 Receptors in Living Subjects

• Published in: Journal of medicinal chemistry Vol. 55; no. 19; pp. 8272 - 8282
• Main Authors: James, Michelle L, Shen, Bin, Zavaleta, Cristina L, Nielsen, Carsten H, Mesangeau, Christophe, Vuppala, Pradeep K, Chan, Carmel, Avery, Bonnie A, Fishback, James A, Matsumoto, Rae R, Gambhir, Sanjiv S, McCurdy, Christopher R, Chin, Frederick T
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11.10.2012
• Subjects: Animals; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacokinetics; Benzothiazoles - chemical synthesis; Benzothiazoles - chemistry; Benzothiazoles - pharmacokinetics; Bone and Bones - diagnostic imaging; Bone and Bones - metabolism; Brain - diagnostic imaging; Brain - metabolism; CHO Cells; Cricetinae; Cricetulus; Fluorine Radioisotopes; In Vitro Techniques; Liver - diagnostic imaging; Liver - metabolism; Mice; Mice, Inbred BALB C; Positron-Emission Tomography; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Rats; Receptors, sigma - metabolism; Sigma-1 Receptor; Tissue Distribution
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm300371c

σ-1 receptor (S1R) radioligands have the potential to detect and monitor various neurological diseases. Herein we report the synthesis, radiofluorination, and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([18F]FTC-146, [18F]13). [18F]13 was synthesized by nucleophilic fluorination, affording a product with >99% radiochemical purity (RCP) and specific activity (SA) of 2.6 ± 1.2 Ci/μmol (n = 13) at end of synthesis (EOS). Positron emission tomography (PET) and ex vivo autoradiography studies of [18F]13 in mice showed high uptake of the radioligand in S1R rich regions of the brain. Pretreatment with 1 mg/kg haloperidol (2), nonradioactive 13, or BD1047 (18) reduced the binding of [18F]13 in the brain at 60 min by 80%, 82%, and 81%, respectively, suggesting that [18F]13 accumulation in mouse brain represents specific binding to S1Rs. These results indicate that [18F]13 is a promising candidate radiotracer for further evaluation as a tool for studying S1Rs in living subjects.