Modeling considerations for 11C-CUMI-101, an agonist radiotracer for imaging serotonin 1A receptor in vivo with PET.
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.


CONCLUSIONS
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.
Milak
Matthew S
MS
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA. mm2354@columbia.edu
Severance
Alin J
AJ
Ogden
R Todd
RT
Prabhakaran
Jaya
J
Kumar
J S Dileep
JS
Majo
Vattoly J
VJ
Mann
J John
JJ
Parsey
Ramin V
RV
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D002250:Carbon Radioisotopes; D008297:Male; D008954:Models, Biological; D010215:Papio; D010879:Piperazines / Q000378:metabolism; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000378:metabolism; D019275:Radiopharmaceuticals; D044282:Receptor, Serotonin, 5-HT1A / Q000032:analysis*; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D014227:Triazines
C529131:2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5-(2H,4H)-dione; D002250:Carbon Radioisotopes; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D014227:Triazines; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin