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

2008; Society of Nuclear Medicine and Molecular Imaging; Volume: 49; Issue: 4 Linguagem: Inglês

10.2967/jnumed.107.046540

1535-5667

Matthew S. Milak, Alin J. Severance, R. Todd Ogden, Jaya Prabhakaran, J.S. Dileep Kumar, Vattoly J. Majo, J. John Mann, Ramin V. Parsey,

Medical Imaging Techniques and Applications

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 Alzheimer9s 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(2 H ,4 H )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 ± 43.0 (4.50 ± 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 = B max /K d ) (B max = maximum number of binding sites; K d = dissociation constant) as the outcome measure. Arterial blood sampling and metabolite-corrected 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, within-subject 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% ± 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% ± 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 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.