Synthesis and Biological Evaluation of 99mTc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging

With a poor prognosis, glioblastoma multiforme is the most aggressive tumor of the central nervous system in humans. The aim of this study was to develop novel tracers for the tumor targeting and imaging of overexpressed serotonin-7 receptors (5-HT(7)Rs) in U-87 MG glioma xenografted nude mice. Two phenylpiperazine derivatives named as PHH and MPHH were designed, and the corresponding radiotracers Tc-99m-PHH and Tc-99m-MPHH were synthesized in high radiochemical purity (>95%). Tc-99m-MPHH showed a higher affinity to 5-HT7Rs on U-87 MG cells compared to Tc-99m-PHH. In biodistribution studies, the radiocomplexes showed good brain uptake at 15 min combined with good radioactivity retention in the brain for 240 min. Regional rabbit brain studies indicated a higher radioactivity concentration in the hippocampus and diencephalon than in the cerebellum. Compared to Tc-99m-MPHH, the Tc-99m-PHH exhibited a significantly increased tumor uptake at 15 and 60 min, but the rapid blood clearance of Tc-99m-MPHH led to enhanced tumor-to-muscle ratios at 240 min. A significant reduction in tumor uptake 60 min after an injection of pimozide (5-HT7 receptor antagonist) confirms the tumor uptake was receptor-mediated specifically. The tumor-to-contralateral muscle tissue ratio of Tc-99m-PHH and Tc-99m-MPHH in nude mice with U-87 MG xenograft was measured (5.25 and 4.65) at 60 min as well as (6.25 and 6.76) at 240 min, respectively.

Automated summary

This study aimed to develop novel tracers for targeting and imaging overexpressed serotonin-7 receptors in U-87 MG glioma xenografted nude mice. The radiotracers Tc-99m-PHH and Tc-99m-MPHH showed promising affinity and uptake in the tumor tissue, with Tc-99m-MPHH demonstrating higher affinity to 5-HT7Rs.