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‐HT7  receptor, the most recently identified member of 5‐HT receptor family dysregulation has an association with var...

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Bibliographic Details
Published in:Drug development research 2022-06, Vol.83 (4), p.1024-1033
Main Authors: Kumari, Neelam, Adhikari, Anupriya, Singh, Deepika, Bhagat, Sunita, Ojha, Himanshu, Tiwari, Anjani K.
Format: Article
Language:English
Subjects:
Animal models
Autoradiography
benzoxazolone
Brain
Central nervous system
Cerebellum
Cerebral cortex
Epilepsy
Hippocampus
Ligands
long chain arylpiperazine
Mental disorders
Methylation
Neurological diseases
Optimization
PET
Positron emission
Positron emission tomography
Radioactivity
Radiochemistry
Receptors
Schizophrenia
serotonin receptors
Sodium hydroxide
Substitutes
Synthesis
Tomography
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Summary: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‐HT7  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. [11C]ABO was obtained by O‐methylation of desmethyl‐precursor using [11C]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 [11C]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 µM 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 [11C]ABO. In summary, these pieces of data designate [11C]ABO as a promising 5‐HT7 receptor ligand that can have possible roles in clinics after its further optimization on different animal models.
ISSN:0272-4391
1098-2299
DOI:10.1002/ddr.21930