Carbon-11 Isotopic Labeling and PET Evaluation of Serodolin: A β-Arrestin-Biased Ligand with Antinociceptive Properties.

Serodolin is a biased agonist of the 5-HT7 receptors that has demonstrated promising antinociceptive properties in preclinical models. To further support the development of this potential drug, we decided to use PET imaging to demonstrate in vivo the capacity of Serodolin to cross the blood-brain barrier and bind specifically in the brain. For that matter, Serodolin was isotopically radiolabeled with carbon-11 (β+, t1/2 = 20.4 min) using the Staudinger/aza-Wittig strategy and an azide precursor synthesized in 3 steps with an 18% yield. After optimization, automated radiosynthesis afforded [11C]Serodolin in 79 ± 4% decay-corrected radiochemical yield (n = 6) within 30 min. Quality control performed by analytical HPLC showed that ready-to-inject [11C]Serodolin was obtained with over 95% radiochemical and chemical purities and a molar activity of 55 ± 3 GBq/μmol (n = 6). Blood kinetics of [11C]Serodolin performed with and without coinjection of nonradioactive Serodolin (5 mg/kg) in healthy rats displayed a rapid distribution (1.25 min) and fast systemic clearance with no significant difference between the tracer and pharmacological doses. Brain PET imaging and kinetics in healthy rats showed a rapid accumulation of [11C]Serodolin (Cmax = 1.70 ± 0.35 standard uptake value at 3 min postinjection) and a widespread distribution throughout the brain parenchyma, whereas coinjection with nonradioactive Serodolin (5 mg/kg) resulted in a generalized and significant (p = 0.000012, two-way ANOVA) reduction of brain exposure (area under the curve (0-60) < 30%). These results demonstrate for the first time in vivo a reduced brain exposure under pharmacological coinjection, consistent with central target engagement of Serodolin, and encourage further development of this molecule as a potential antinociceptive drug.