Benzoxazolone-arylpiperazinyl scaffold-based PET ligand for 5-HT7: Synthesis and biological evaluation

Efforts are underway to improve the diagnosis and treatment for neurological disorders like depression, anxiety, epilepsy, and schizophrenia. The G-protein-coupled receptors (GPCRs) 5-HT(7 )receptor, the most recently identified member of 5-HT receptor family dysregulation has an association with various central nervous system (CNS) disorders and its ligands have an edge as potential therapeutics. Here, we report the synthesis, characterization, and biological evaluation of diversely substituted methoxy derivatives of 2-benzoxazolone arylpiperazine for targeting 5-HT7 receptors. Out of all derivatives, only C-2 substituted derivative, 3-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)benzoxazol-2(3H)-one/ABO demonstrate a high affinity for human 5-HT7 receptors. [C-11]ABO was obtained by O-methylation of desmethyl-precursor using [C-11]CH3OTf in the presence of NaOH giving a high radiochemical yield of 25 +/- 12% (decay-corrected, n = 7) with stability up to 1.5 h postradiolabeling. In vitro autoradiography displays binding of [C-11]ABO in accordance with 5-HT7 distribution with a decrease of approximately 80% and 40% activity in the hippocampus and cerebellum brain region when administered with 10 mu M cold ligand. Prefatory positron emission tomography scan results in Sprague-Dawley (SD) rat brain revealed fast and high radioactivity build-up in 5-HT7 receptor-rich regions, namely, the hippocampus (2.75 +/- 0.16 SUV) and the cerebral cortex (2.27 +/- 0.02 SUV) establishing selective targeting of [C-11]ABO. In summary, these pieces of data designate [C-11]ABO as a promising 5-HT(7 )receptor ligand that can have possible roles in clinics after its further optimization on different animal models.

Automated summary

Efforts are being made to improve the diagnosis and treatment of neurological disorders such as depression, anxiety, epilepsy, and schizophrenia. This study focuses on the 5-HT7 receptor and its potential for targeted therapy. The synthesis, characterization, and biological evaluation of various methoxy derivatives of 2-benzoxazolone arylpiperazine were conducted, and the C-2 substituted derivative showed high affinity for human 5-HT7 receptors.