Synthesis and evaluation of 99m Tc-labeled 1-(2-Pyridyl)piperazine derivatives as radioligands for 5HT 7 receptors.

Glioblastoma multiform (GBM) is one of the most aggressive tumors of the central nervous system in humans. GBM overexpresses serotonin-7 receptors (5-HTRs); hence, this study aims to develop 5-HTR targeted radiotracers. Aryl piperazine derivatives can act as ligands for 5-HTR. Therefore, compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were synthesized and radiolabeled with TcN core. Radiolabeled 6 and 7 (TcN-[6] and TcN-[7]) were prepared with high radiochemical purity (RCP > 96%). They displayed high affinity toward U-87 MG cell line 5-HTR. The calculated K for TcN-[7] was lower than that of TcN-[6] (14.85 ± 0.32 vs 22.57 ± 0.73 nM) which indicates the higher affinity of TcN-[7] toward 5-HTR. A molecular docking study also confirmed the binding of these radiotracers to 5-HTR. The biodistribution study in normal mice revealed that TcN-[7] has the highest brain accumulation at 30 min post-injection (0.54 ± 0.12 %ID/g) while the uptake of TcN-[6] is much lower (0.14 ± 0.02 %ID/g). The biodistribution study in the xenograft model confirms that the radiotracers recognize the tumor site. TcN-[6], and TcN-[7] showed the highest tumor uptake at 1-hour post-injection (5.44 ± 0.58 vs 4.94 ± 1.65 %ID/g) and tumor-to-muscle ratios were (4.61 vs. 5.61). The injection of pimozide blocks the receptors and significantly reduces the tumor-to-muscle ratios at 1-hour post-injection to 0.81 and 0.31, respectively. In correlation with in vitro study, TcN-[6] and TcN-[7] visualize the tumor site in U-87 MG glioma xenografted nude mice and display the tumor-to-muscle ratios of 7.05 and 6.03.