Modeling Considerations for ^sup 11^C-CUMI-101, an Agonist Radiotracer for Imaging Serotonin 1A Receptor In Vivo with PET

• Published in: The Journal of nuclear medicine (1978) Vol. 49; no. 4; p. 587
• Main Authors: Milak, Matthew S, Severance, Alin J, Ogden, R Todd, Prabhakaran, Jaya, Kumar, J S Dileep, Majo, Vattoly J, Mann, J John, Parsey, Ramin V
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01-04-2008
• Subjects: Experiments; Health services; Human subjects; Medical research; Plasma; Studies
• EISSN: 1535-5667
• ISSN: 0161-5505

Several lines of evidence demonstrate involvement of serotonin 1A receptors (5-HT^sub 1A^Rs) in the pathophysiology of neuropsychiatrie disorders such as depression, suicidal behavior, schizophrenia, and Alzheimer's disease. We recently published the synthesis and initial evaluation of [O-methyl-^sup 11^C]2-(4-(4-(2methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5 (2H,4H)dione (^sup 11^C-MMP), a 5-HT^sub 1A^R agonist. Here we determine the optimal modeling parameters for ^sup 11^C-MMP under its new name, ^sup 11^C-CUMI-101, in Papio anubis. Methods: PET scans were performed on 2 adult male P. anubis; 166.5 MBq ± 43.0 (4.50 ± 1.16 mCi) of ^sup 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^sub F^ = B^sub max^/K^sub d^) (B^sub max^ = maximum number of binding sites; K^sub d^ = dissociation constant) as the outcome measure. Arterial blood sampling and metabolitecorrected arterial input function were used for full quantification of BP^sub 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; identifiabiltty 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^sub 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^sub 1A^ agonist 8-hydroxy-2-(di-n-propylamino) tetralin) [8-OH-DPAT] 2 mg/kg, intravenous). Results: All metabolites are more polar than ^sup 11^C-CUMI-101, and no significant change in metabolites was observed in the blocking studies. The free fraction is 59% ± 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^sub F^ is 11.15% ± 4.82% across all regions, WSMSS = 2.66, variance = 6.07, ICC = 0.43, and bootstrap identifiability = 0.59. Preadministration of WAY100635 and 8-OH-DPAT resulted in 87% and 76% average reductions in BP^sub 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, ^sup 11^C-CUMI-101 is an excellent candidate for imaging high-affinity 5-HT^sub 1A^Rs in humans. [PUBLICATION ABSTRACT]