The serotonin (5-hydroxytryptamine, or 5-HT) type 1A receptor (5-HT1AR) is implicated in the pathophysiology of numerous neuropsychiatric disorders. We have published the initial evaluation and reproducibility in vivo of [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5 (2H,4H)dione (11C-CUMI-101), a novel 5-HT1A agonist radiotracer, in Papio anubis. Here, we report the optimal modeling parameters of 11C-CUMI-101 for human PET studies. Methods PET scans were obtained for 7 adult human volunteers. 11C-CUMI-101 was injected as an intravenous bolus, and emission data were collected for 120 min in 3-dimensional mode. We evaluated 10 different models using metabolite-corrected arterial input functions or reference region approaches and several outcome measures. Results When using binding potential (BPF = Bavail/KD [total available receptor concentration divided by the equilibrium dissociation constant]) as the outcome measure, the likelihood estimation in the graphical analysis (LEGA) model performed slightly better than the other methods evaluated at full scan duration. The average test–retest percentage difference was 9.90% ± 5.60%. When using BPND (BPND = fnd × Bavail/KD; BPND equals the product of BPF and fnd [free fraction in the nondisplaceable compartment]), the simplified reference tissue method (SRTM) achieved the lowest percentage difference and smallest bias when compared with nondisplaceable binding potential obtained from LEGA using the metabolite-corrected plasma input function (r2 = 0.99; slope = 0.92). The time–stability analysis indicates that a 120-min scan is sufficient for the stable estimation of outcome measures. Voxel results were comparable to region-of-interest–based analysis, with higher spatial resolution. Conclusion On the basis of its measurable and stable free fraction, high affinity and selectivity, good blood–brain barrier permeability, and plasma and brain kinetics, 11C-CUMI-101 is suitable for the imaging of high-affinity 5-HT1A binding in humans.

3-Chloro-1H-indole-2-carboxaldehydes are obtained in moderate yields by the one-pot reaction of various substituted 2-[(carboxymethyl)amino]benzoic acids (1a-d) using Vilsmeier reagent (DMF/POCl(3)). The benzfused acyclic diacids analogous to 1a in which nitrogen was replaced by oxygen and sulfur also underwent the reaction smoothly. 3-Chloro-1H-pyrrole-2,4-dicarboxaldehyde was obtained as the only product by the reaction of N-carboxymethyl beta-alanine.

We identified [11C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT1A receptors in baboons.

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Several lines of evidence demonstrate involvement of serotonin 1A receptors (5-HT 1A Rs) in the pathophysiology of neuropsychiatric disorders such as depression, suicidal behavior, schizophrenia, and Alzheimer's disease. We recently published the synthesis and initial evaluation of [O-methyl-11 C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5 (2H,4H)dione ( 11 C-MMP), a 5-HT 1A R agonist. Here we determine the optimal modeling parameters for 11 C-MMP under its new name, 11 C-CUMI-101, in Papio anubis. Methods: PET scans were performed on 2 adult male P. anubis; 166.5 MBq 6 43.0 (4.50 6 1.16 mCi) of 11 C-CUMI-101 were injected as an intravenous bolus, and emission data were collected for 120 min in 3-dimensional mode. We evaluated 4 different models (1-and 2-tissue compartment iterative and noniterative kinetic models, basis pursuit, and likelihood estimation in graphical analysis [LEGA]), using binding potential (BP F 5 B max /K d ) (B max 5 maximum number of binding sites; K d 5 dissociation constant) as the outcome measure. Arterial blood sampling and metabolitecorrected arterial input function were used for full quantification of BP F . To assess the performance of each model, we compared results using 6 different metrics (percentage difference, withinsubject mean sum of squares [WSMSS] for reproducibility; variance across subjects, intraclass correlation coefficient [ICC] for reliability; identifiability based on bootstrap resampling of residuals; and time stability analysis to determine minimal required scanning time) at each of 6 different scanning durations. Models were also evaluated on scans acquired after injecting the 5-HT 1A antagonist [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide] [WAY100635] 0.5 mg/kg, intravenous) and the 5-HT 1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin) [8-OH-DPAT] 2 mg/kg, intravenous). Results: All metabolites are more polar than 11 C-CUMI-101, and no significant change in metabolites was observed in the blocking studies. The free fraction is 59% 6 3%. We determined that 100 min of scanning time is adequate and that for the region-of-interest (ROI)-level analysis, the LEGA model gives the best results. The median test-retest percentage difference for BP F is 11.15% 6 4.82% across all regions, WSMSS 5 2.66, variance 5 6.07, ICC 5 0.43, and bootstrap identifiability 5 0.59. Preadministration of WAY100635 and 8-OH-DPAT resulted in 87% and 76% average reductions in BP F values, respectively, across ROIs. Conclusion: On the basis of the measurable free fraction, high affinity and selectivity, adequate blood-brain permeability, and favorable plasma and brain kinetics, 11 C-CUMI-101 is an excellent candidate for imaging high-affinity 5-HT 1A Rs in humans.