2-(2′-((Dimethylamino)methyl)-4′-(3-[18F]fluoropropoxy)-phenylthio)benzenamine for positron emission tomography imaging of serotonin transporters

IntroductionA new 18F ligand, 2-(2′-((dimethylamino)methyl)-4′-(3-[18F]fluoropropoxy)-phenylthio)benzenamine ([18F]1), for positron emission tomography (PET) imaging of serotonin transporters (SERT) was evaluated.MethodsBinding affinity was determined through in vitro binding assays with LLC-PK1 cells overexpressing SERT, NET or DAT (LLC-SERT, LLC-NET and LLC-DAT) and with rat cortical homogenates. Localization and selectivity of [18F]1 binding in vivo were evaluated by biodistribution, autoradiography and A-PET imaging studies in rats.ResultsThis compound displayed excellent binding affinity for SERT in vitro with Ki=0.33 and 0.24 nM in LLC-SERT and rat cortical homogenates, respectively. Biodistribution studies with [18F]1 showed good brain uptake (1.61% dose/g at 2 min postinjection), high uptake into the hypothalamus (1.22% dose/g at 30 min) and a high target-to-nontarget (hypothalamus to cerebellum) ratio of 9.66 at 180 min postinjection. Pretreatment with a SERT selective inhibitor considerably inhibited [18F]1 binding in biodistribution studies. Ex vivo autoradiography reveals [18F]1 localization to brain regions with high SERT density, and this binding was blocked by pretreatment with SERT selective inhibitors. Small animal PET (A-PET) imaging in rats provided clear images of tracer localization in the thalamus, midbrain and striatum. In A-PET chasing experiments, injecting a SERT selective inhibitor 75 min post-tracer injection causes a dramatic reduction in regional radioactivity and the target-to-nontarget ratio.ConclusionThe results of the biological studies and the ease of radiosynthesis with moderately good radiochemical yield (RCY=10–35%) make [18F]1 an excellent candidate for SERT PET imaging.