Development of a High-Affinity PET Radioligand for Imaging Cannabinoid Subtype 2 Receptor

• Published in: Journal of medicinal chemistry Vol. 59; no. 17; pp. 7840 - 7855
• Main Authors: Moldovan, Rareş-Petru, Teodoro, Rodrigo, Gao, Yongjun, Deuther-Conrad, Winnie, Kranz, Mathias, Wang, Yuchuan, Kuwabara, Hiroto, Nakano, Masayoshi, Valentine, Heather, Fischer, Steffen, Pomper, Martin G, Wong, Dean F, Dannals, Robert F, Brust, Peter, Horti, Andrew G
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.09.2016; Amer Chemical Soc
• Subjects: Animals; Blood-Brain Barrier - metabolism; Brain - diagnostic imaging; Brain - metabolism; Chemistry, Medicinal; Female; Fluorine Radioisotopes; Imines - chemical synthesis; Imines - chemistry; Imines - pharmacokinetics; Inflammation - diagnostic imaging; Inflammation - metabolism; Life Sciences & Biomedicine; Ligands; Lipopolysaccharides - pharmacology; Mice; Neuroimaging; Pharmacology & Pharmacy; Positron-Emission Tomography; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Receptor, Cannabinoid, CB2 - metabolism; Science & Technology; Spleen - diagnostic imaging; Spleen - metabolism; Stereoisomerism; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacokinetics; Tissue Distribution; CB2 RECEPTORS; IN-VITRO; POSITRON-EMISSION-TOMOGRAPHY; HUMAN BRAIN; MULTIPLE-SCLEROSIS; LIGANDS; ACID AMIDE HYDROLASE; HEALTHY-SUBJECTS; TYPE-2 RECEPTOR; EXPRESSION
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00554

Cannabinoid receptors type 2 (CB2) represent a target with increasing importance for neuroimaging due to its upregulation under various pathological conditions. Encouraged by preliminary results obtained with [11C]­(Z)-N-(3-(2-methoxyethyl)-4,5-dimethylthiazol-2­(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide ([11C]­A-836339, [11C]1) in a mouse model of acute neuroinflammation (induced by lipopolysaccharide, LPS), we designed a library of fluorinated analogues aiming for an [18F]-labeled radiotracer with improved CB2 binding affinity and selectivity. Compound (Z)-N-(3-(4-fluorobutyl)-4,5-dimethylthiazol-2­(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (29) was selected as the ligand with the highest CB2 affinity (K i = 0.39 nM) and selectivity over those of CB1 (factor of 1000). [18F]29 was prepared starting from the bromo precursor (53). Specific binding was shown in vitro, whereas fast metabolism was observed in vivo in CD-1 mice. Animal PET revealed a brain uptake comparable to that of [11C]1. In the LPS-treated mice, a 20–30% higher uptake in brain was found in comparison to that in nontreated mice (n = 3, P < 0.05).