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

Abstract

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-HT₇Rs) in U-87 MG glioma xenografted nude mice. Two phenylpiperazine derivatives named as <b>PHH</b> and <b>MPHH</b> were designed, and the corresponding radiotracers ^99mTc-<b>PHH</b> and ^99mTc-<b>MPHH</b> were synthesized in high radiochemical purity (>95%). ^99mTc-<b>MPHH</b> showed a higher affinity to 5-HT₇Rs on U-87 MG cells compared to ^99mTc-<b>PHH</b>. 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 ^99mTc-<b>MPHH</b>, the ^99mTc-<b>PHH</b> exhibited a significantly increased tumor uptake at 15 and 60 min, but the rapid blood clearance of ^99mTc-<b>MPHH</b> 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 ^99mTc-<b>PHH</b> and ^99mTc-<b>MPHH</b> 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.