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.

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.

Comparison of high and low affinity serotonin 1A receptors by PET in vivo in nonhuman primates.

Serotonin (5-HT) 1A receptors exist in high and low affinity states. Agonist ligands bind preferentially to the high affinity state receptors, providing a more functionally relevant measure than antagonist binding. We now report comparison of 5-HT(1A) binding in vivo using both [¹¹C]CUMI-101 (agonist) and [¹¹C]WAY100635 (antagonist) in nonhuman primates. PET studies show that both tracers bind to known 5-HT(1A) receptor (5-HT(1A)R)-rich regions of baboon brain. The binding (BP(F)) of [¹¹C]CUMI-101 was lower on an average of 55% across the regions of interest (ROIs) compared to [¹¹C]WAY100635. This ratio is consistent with the in vitro binding data of agonist and antagonist 5-HT(1A)R ligands previously reported.

Synthesis and in vivo evaluation of [11C]MPTQ: a potential PET tracer for alpha2A-adrenergic receptors.

Radiosynthesis and in vivo evaluation of [N-methyl-(11)C] 5-methyl-3-[4-(3-phenylallyl)-piperazin-1-ylmethyl]-3,3a,4,5-tetrahydroisoxazolo[4,3-c]quinoline (1), a potential PET tracer for alpha2-adrenergic receptors is described. Syntheses of nonradioactive standard 1 and corresponding desmethyl precursor 2 were achieved from 2-aminobenzaldehyde in 40% and 65% yields, respectively. Methylation using [(11)C]CH(3)I in presence of aqueous potassium hydroxide in DMSO afforded [(11)C]1 in 25% yield (EOS) with >99% chemical and radiochemical purities with a specific activity ranged from 3-4 Ci/micromol (n=6). The total synthesis time was 30 min from EOB. PET studies in anesthetized baboon show that [(11)C]1 penetrates BBB and accumulates in alpha2A-AR enriched brain areas.

Synthesis, in vitro and in vivo evaluation of [11C]MMTP: a potential PET ligand for mGluR1 receptors.

Synthesis, in vitro and in vivo evaluation of [O-methyl-(11)C]dimethylamino-3(4-methoxyphenyl)-3H-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-one (1), a potential imaging agent for mGluR1 receptors using PET are described. Synthesis of the corresponding desmethyl precursor 2 was achieved by demethylation of the methoxyphenyl compound 1 in 90% yield. Methylation using [(11)C]MeOTf in presence of NaOH afforded [(11)C]1 in 30% yield (EOS) with >99% chemical and radiochemical purities and with a specific activity of 3-5Ci/micromol (n=6). The total synthesis time was 30min from EOB. The radiotracer selectively labeled mGluR1 receptors in slide-mounted sections of postmortem human brain containing cerebellum, hippocampus, prefrontal cortex and striatum as demonstrated by in vitro autoradiography using phosphor-imaging. PET studies in anesthetized baboon show that [(11)C]1 penetrates the BBB and accumulates in cerebellum, a region reported to have higher expression of mGluR1. These findings suggest [(11)C]1 is a promising PET radiotracer candidate for mGluR1.