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-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; Emax = 77%; EC50 = 0.65 nM) 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 [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 WAY100,635. 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.

Synthesis and in vitro evaluation of [18F]FECIMBI-36: A potential agonist PET ligand for 5-HT2A/2C receptors

“…22 The [ 18 F]FEOTs in turn was synthesized by a procedure previously reported by us. 23 Total synthesis and purification time required for the radiosynthesis was 50 min at EOS ( N = 6). The specific activity of the radioproduct was 1–2 Ci/μmol at EOS.…”

Autoradiographic Evaluation of [18F]FECUMI-101, a High Affinity 5-HT1AR Ligand in Human Brain

“…In contrast, in vivo PET imaging in baboon did not distinguish CA1 and DG subfields and only measured whole hippocampus. 16 In 16 These findings are in contrast to the parent ligand [ 3 H]CUMI-101 (5-HT 1A R K i = 0.15 nM; α 1 R K i = 6.5 nM), which shows high amounts of specific binding in 5-HT 1A R rich brain regions and no significant binding to α 1 R except for a small level of binding in DG. 13 The reason for why there is more binding of Figure 3).…”

“…32 1,3,17 Receptor selectivity assays show that the highest affinity of FECUMI-101, apart from 5-HT 1A R (K i = 0.1 nM), is to 5-HT 7 R (K i = 17.2 nM), α 1A R (K i = 21.4 nM), and α 1B R (26.8 nM). 16 Both 5-HT 7 R and α 1 R are abundant in the thalamus, and α 1 R is coexpressed with 5-HT 1A R in many brain regions. 18−20 Since α 1 R antagonists are known to produce cardiovascular changes even at 0.01 mg/kg doses in monkeys, it is difficult to perform in vivo blocking experiments to test α 1A R selectivity of [ 18 F]1 in nonhuman primates.…”

“…16 Radiosynthesis of [ 18 F]FECUMI-101 was achieved with minor modifications of the reported procedure. 16 Briefly, [ 18 F]fluoroethyl tosylate was synthesized and reacted with the corresponding desethyl precursor in DMSO in the presence of K 2 CO 3 . The crude product was purified by semipreparative HPLC, followed by elution with C-18 Sep-Pak cartridge, and the radioproduct was reconstructed in ethanol.…”

Synthesis and evaluation of arylpiperazines derivatives of 3,5-dioxo-(2 H ,4 H )-1,2,4-triazine as 5-HT 1A R ligands

“…24, 25 We have recently identified several high affinity and selective 5-HT 1A R ligands as candidates for PET ligands. 26–29 Of these [ 11 C]CUMI-101, is the only successful partial agonist PET tracer available so far for the in vivo measurement of high affinity 5-HT 1A R agonist binding in nonhuman primates and human subjects with PET. 26, 30–33 The characteristic feature of the ligands we identified is the presence of a 3,5-dioxo-(2 H ,4 H )-1,2,4-triazine skeleton tethered to an arylpiperazine unit through a C-4 alkyl side chain.…”