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

Abstract The 5-HT 1A R partial agonist PET radiotracer, [ 11 C]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(2 H ,4 H )dione (FECUMI-101) ( K i  = 0.1 nM; E max  = 77%; EC 50  = 0.65 nM) as a partial agonist 5-HT 1A R ligand of the parent ligand CUMI-101. FECUMI-101 is radiolabeled with F-18 by O -fluoroethylation of the corresponding desmethyl analogue ( 1 ) with [ 18 F]fluoroethyltosylate in DMSO in the presence of 1.6 equiv of K 2 CO 3 in 45 ± 5% yield (EOS). PET shows [ 18 F]FECUMI-101 binds specifically to 5-HT 1A R enriched brain regions of baboon. The specificity of [ 18 F]FECUMI-101 binding to 5-HT 1A R was confirmed by challenge studies with the known 5-HT 1A R ligand WAY100635. These findings indicate that [ 18 F]FECUMI-101 can be a viable agonist ligand for the in vivo quantification of high affinity 5-HT 1A R with PET.