Fluorine-18 labeled diphenyl sulfide derivatives for imaging serotonin transporter (SERT) in the brain

Serotonin transporters (SERT) play an important role in controlling serotonin concentration in the synaptic cleft and in managing postsynaptic signal transduction. Inhibitors of SERT binding are well known as selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, paroxetine, and escitalopram, that are commonly prescribed antidepressants. Positron emission tomography (PET) and single photon emission tomography (SPECT) imaging agents targeting SERT may be useful for studying its function and providing a tool for monitoring drug treatment.

A series of novel ¹⁸F-labeled diphenyl sulfide derivatives were prepared and tested for their binding affinity. Among them, 2-((2-((dimethylamino)-methyl)-4-(2-(2-fluoroethoxy)ethoxy)phenyl)thio)aniline, 1, which showed excellent binding toward serotonin transporter (SERT) in the brain (K_i = 0.09 nM), was selected for further evaluation. An active OTs intermediate, 7, was treated with [¹⁸F]F^-/K₂₂₂ to provide [¹⁸F]1 in one step and in high radiochemical yields. This new SERT targeting agent was evaluated in rats by biodistribution studies and animal PET imaging studies.

The radiolabeling reaction led to the desired [¹⁸F]1. After HPLC purification no-carrier-added [¹⁸F]1 was obtained (radiochemical yield, 23-47% (n = 10,); radiochemical purity >99%; molar activity, 15-28 GBq/μmol). Biodistribution studies with [¹⁸F]1 showed good brain uptake (1.04% dose/g at 2 min post-injection), high uptake into the hypothalamus (1.55% dose/g at 30 min), and a high target-to-non-target (hypothalamus to cerebellum) ratio of 6.1 at 120 min post-injection. A PET imaging study in normal rats showed excellent uptake in the midbrain and thalamus regions known to be rich in SERT binding sites at 60 min after iv injection. Chasing experiment with escitalopram (iv, 2 mg/kg) in a rat at 60 min after iv injection caused a noticeable reduction in the regional radioactivity and the target-to-non-target ratio, suggesting binding by [¹⁸F]1 was highly specific and reversible for SERT binding sites in the brain.

A novel diphenyl sulfide derivative, [¹⁸F]1 for SERT imaging was successfully prepared and evaluated. Results suggest that this new chemical entity is targeting SERT binding sites in the brain, and it is a suitable candidate for future commercial development.