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, 21 (17), 5598-604

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

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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

Vattoly J Majo et al. Bioorg Med Chem.

Abstract

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.

Keywords: 5-HT1AR; Agonist; Brain; FECUMI-101; PET; Radiotracer.

Figures

Figure 1
Figure 1
Unmetabolized parent fraction of [18F]FECUMI-101 in baboon plasma.
Figure 2
Figure 2
Sum of 60–180 minute of [18F]FECUMI-101 image in baboon 1st row: Base line; 2nd row: Chase with WAY100635. First column: sagittal, middle column: coronal, last column: axial views.
Figure 3
Figure 3
Baseline time activity curves of [18F]FECUMI-101 in baboon AMY = Amygdala, CAU = Caudate, CER = cerebellum, CIN = cingulate, HIP = hippocampus, PFC = prefrontal cortex, TEM: temporal cortex, INS: insular cortex, THA: thalamus, ACN: anterior cingulate
Figure 4
Figure 4
Time activity curves of [18F]FECUMI-101 in baboon after WAY100635 chase
Scheme 1
Scheme 1
Radiosynthesis of [18F]FECUMI-101

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