Abstract
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Objectives Sertraline hydrochloride (Zoloft®, Pfizer) is a widely used antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The aims of this study were to develop [11C]sertraline and evaluate its in vivo distribution and kinetic models in the human brains.
Methods The [11C]sertraline was synthesized by [11C]methylation of desmethyl (S)-sertraline using [11C]methyl triflate. Dynamic PET (duration: 90~120 min) and 3D T1 SPGR MRI scans were performed in 5 healthy male volunteers (mean age 32.4 y, range 21 - 43 y). During the PET scans, arterial blood samples were intermittently collected to determine input function. The fraction of radio-labeled metabolite was analyzed using HPLC, and the fraction of plasma protein binding was measured by ultra-filtration. Tissue time-activity curves (CT) were obtained from 7 brain regions using MRI and probabilistic volumes of interest. Goodness-of-fit for CT using 2-compartment model (K1 and k2; 2C2P) and 3-compartment models with irreversible (K1-k3; 3C3P) and reversible (K1-k4; 3C4P) receptor binding were compared.
Results In the blood, the fraction of radio-labeled metabolite was negligibly small. The average unbound fraction in plasma was 16.5% at 30 min after tracer injection. Akaike information criteria (AIC) analysis showed that the 2C2P was the most suitable model for describing CT. Average values of K1 (ml/min/g) and k2 (1/min) estimated using this model were 0.54 and 0.012 in putamen and 0.43 and 0.016 in cerebellum. The k3 and k4 were negligibly small in the 3-compartment models.
Conclusions The results demonstrate the [11C]sertraline has high distribution volume in human brain due to its fast uptake and slow clearance and/or dissociation, and 2-compartment model is suitable for its kinetic modeling studies. This new agent will be useful for pharmacokinetics and pharmacodynamic studies of sertraline