New 99m Tc(CO) 3 -radiolabeled arylpiperazine pharmacophore as potent 5HT 1A serotonin receptor radiotracer: Docking studies, chemical synthesis, radiolabeling, and biological evaluation

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 62; no. 4; pp. 166 - 177
• Main Authors: Erfani, Mostafa, Malek, Hadi, Sadat Ebrahimi, Seyed Esmaeil, Hassanzadeh, Leila
• Format: Journal Article
• Language: English
• Published: England 01.04.2019
• Subjects: Animals; Brain - metabolism; Click Chemistry; Humans; Isotope Labeling; Male; Molecular Docking Simulation; Organotechnetium Compounds - chemistry; Piperazine - chemical synthesis; Piperazine - chemistry; Piperazine - metabolism; Piperazine - pharmacokinetics; Protein Conformation; Radiochemistry; Rats; Receptor, Serotonin, 5-HT2C - chemistry; Receptor, Serotonin, 5-HT2C - metabolism; Tissue Distribution; 2-ethynylpyridine; docking; click chemistry; 1-(2-methoxyphenyl)piperazine (MPP); 5HT1A homology model; WAY100635
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.3709

In spite of previous efforts, there is lack of a radiotracer for imaging the 5HT receptor density in human brain, which is involved in several neurological brain disorders. The aim of this study was to prepare a new derivative of 1-(2-methoxyphenyl)piperazine (MPP) as a main chemical structure of 5HT receptor antagonist with 3-carbon linker and radiolabeled by [ Tc][Tc(CO) (H O) ] precursor. Docking studies before chemical synthesis showed similar fashion of interaction for both WAY100635 (potent 5HT receptor antagonist) and new designed ligand, despite of addition of Tc(CO) group in the structure of new ligand. MPP-(CH ) -N was synthesized via three efficient and reliable chemical synthesis steps (more than 80% yield) then radiolabeled by addition of 2-ethynylpyridine and [ Tc][Tc(CO) (H O) ] precursor in one pot procedure (more than 95% radiochemical efficiency) through click chemistry method. After incubation, radiotracer was found stable in vitro up to 2 hours. Binding assays showed about 33% specific binding of radiotracer to the 5HT receptors. Brain biodistribution studies indicated (0.26 ± 0.05)% ID/g hippocampus uptake at 30 minutes post injection, which its specificity was verified through blocking studies. These results suggested that new designed radioligand might serve as a potent SPECT imaging agent to estimate status of 5HT receptors.