Synthesis and in vivo evaluation of [18F]2-(4-(4-(2-(2- fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H) -dione ([18F]FECUMI-101) as an imaging probe for 5-HT1A receptor agonist in nonhuman primates

摘要

The 5-HT1AR partial agonist PET radiotracer, [ 11C]CUMI-101, has advantages over an antagonist radiotracer as it binds preferentially to the high affinity state of the receptor and thereby provides more functionally meaningful information. The major drawback of C-11 tracers is the lack of cyclotron facility in many health care centers thereby limiting widespread clinical or research use. We identified the fluoroethyl derivative, 2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1, 2,4-triazine-3,5(2H,4H)dione (FECUMI-101) (Ki = 0.1 nM; E max = 77%; EC50 = 0.65 nM) as a partial agonist 5-HT 1AR ligand of the parent ligand CUMI-101. FECUMI-101 is radiolabeled with F-18 by O-fluoroethylation of the corresponding desmethyl analogue (1) with [18F]fluoroethyltosylate in DMSO in the presence of 1.6 equiv of K2CO3 in 45 ± 5% yield (EOS). PET shows [ 18F]FECUMI-101 binds specifically to 5-HT1AR enriched brain regions of baboon. The specificity of [18F]FECUMI-101 binding to 5-HT1AR was confirmed by challenge studies with the known 5-HT1AR ligand WAY100635. These findings indicate that [ 18F]FECUMI-101 can be a viable agonist ligand for the in vivo quantification of high affinity 5-HT1AR with PET.