Modeling Considerations for 11C-CUMI-101, an Agonist Radiotracer for Imaging Serotonin 1A Receptor In Vivo with PET
Matthew S. Milak 1*,
Alin J. Severance 2,
R. Todd Ogden 3,
Jaya Prabhakaran 2,
J.S. Dileep Kumar 1,
Vattoly J. Majo 2,
J. John Mann 4,
and
Ramin V. Parsey 1
1 Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Department of Molecular Imaging, New York State Psychiatric Institute, New York, New York
2 Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York
3 Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Department of Molecular Imaging, New York State Psychiatric Institute, New York, New York; Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York
4 Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Department of Molecular Imaging, New York State Psychiatric Institute, New York, New York; Department of Radiology, Columbia University College of Physicians and Surgeons, New York, New York
* To whom correspondence should be addressed. E-mail: mm2354{at}columbia.edu.
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Abstract |
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Several lines of evidence demonstrate involvement of serotonin 1A receptors (5-HT1ARs) 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-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (11C-MMP), a 5-HT1AR agonist. Here we determine the optimal modeling parameters for 11C-MMP under its new name, 11C-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 11C-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 (BPF = Bmax/Kd) (Bmax = maximum number of binding sites; Kd = dissociation constant) as the outcome measure. Arterial blood sampling and metabolite-corrected arterial input function were used for full quantification of BPF. 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-HT1A antagonist [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide] [WAY100635] 0.5 mg/kg, intravenous) and the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin) [8-OH-DPAT] 2 mg/kg, intravenous). Results: All metabolites are more polar than 11C-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 BPF 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 BPF 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, 11C-CUMI-101 is an excellent candidate for imaging high-affinity 5-HT1ARs in humans.
Key Words:
test–retest reproducibility, kinetic modeling, compartment, voxel, bootstrap
