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

• Published in: Bioorganic & medicinal chemistry 2013-09, Vol.21 (17), p.5598-5604
• Main Authors: Majo, Vattoly J, Milak, Matthew S, Prabhakaran, Jaya, Mali, Pratap, Savenkova, Lyudmila, Simpson, Norman R, Mann, J John, Parsey, Ramin V, Kumar, J S Dileep
• Format: Article
• Language: English
• Subjects: Animals; Blood-Brain Barrier - metabolism; Brain - diagnostic imaging; Fluorine Radioisotopes - chemistry; Papio; Piperazines - chemical synthesis; Piperazines - chemistry; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Receptor, Serotonin, 5-HT1A - chemistry; Receptor, Serotonin, 5-HT1A - metabolism; Serotonin 5-HT1 Receptor Agonists - chemical synthesis; Serotonin 5-HT1 Receptor Agonists - chemistry; Triazines - chemical synthesis; Triazines - chemistry
• ISSN: 1464-3391
• DOI: 10.1016/j.bmc.2013.05.050

The 5-HT1AR 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(2H,4H)dione (FECUMI-101) (Ki=0.1nM; Emax=77%; EC50=0.65nM) as a partial agonist 5-HT1AR 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 1.6equiv of K2CO3 in 45±5% yield (EOS). PET shows [(18)F]FECUMI-101 binds specifically to 5-HT1AR enriched brain regions of baboon. The specificity of [(18)F]FECUMI-101 binding to 5-HT1AR was confirmed by challenge studies with the known 5-HT1AR 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-HT1AR with PET.