Abstract
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Objectives Preclinical and early clinical evaluation of serotonin transporter (5HTT) occupancy and displacement by candidate antidepressants is an important part of in vivo characterization in the clinical development of multiple reuptake agents. Such studies aid in prioritization among competing drug candidates and provide rational dosing strategies for Phase 2. The aim of this research is to evaluate 123-I mZIENT, a highly specific imaging biomarker for 5HTT, in both nonhuman primate dose-ranging displacement studies and healthy human dose-ranging occupancy studies using sertraline, a well-characterized 5HTT agent
Methods Ten healthy human subjects underwent 123-I mZIENT SPECT imaging at baseline and after treatment with sertraline (25, 50, or 150 mg po or placebo). Equilibrium distribution volume measurements were assessed in midbrain and expressed as percent change from baseline. Eight 123-I mZIENT studies were performed in 2 baboons assessing sertraline ( range 0.025 – 0.5 mg/kg iv) on midbrain specific binding.
Results In humans sertraline produced 56%, 71%, and 71% midbrain occupancy at doses of 25, 50, and 150 mg, respectively. IV sertraline administration produced dose-dependent reductions in specific binding in non-human primate (range 53%-89%).
Conclusions 123-I mZIENT may be used in translational studies for in vivo characterization of therapeutic agents developed as potential antidepressants. It may be possible to use acute iv displacement paradigms to aid in the prediction of 5HTT occupancy in chronic human dosing studies.
- © 2009 by Society of Nuclear Medicine