99mTc(CO)3-labeled 1-(2-Pyridyl)piperazine derivatives as radioligands for 5HT7 receptors

Abstract The 5-hydroxytryptamine receptor (5-HTR) family involves seven classes of receptors. The 5-HT7R is the newest member of this family and contributes to different physiological and pathological processes. As a pathology, Glioblastoma multiform (GBM) overexpresses 5-HT7R; hence, this study aims to develop radiolabeled aryl piperazine derivatives as 5-HT7R imaging agents. To that end, compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were radiolabeled with fac-[99mTc(CO)3(H2O)3]+ and (99mTc(CO)3-[6] and 99mTc(CO)3-[7]) were obtained with high radiochemical purity (RCP>94%). 99mTc(CO)3-[6] and 99mTc(CO)3-[7] possess high affinity toward 5-HT7R of the U-87 MG cell line. The calculated Ki for them was 26.85±0.78 nM and 36.67±0.89 nM. The biodistribution study in normal mice indicates that the brain uptake of 99mTc(CO)3-[6] and 99mTc(CO)3-[7] is the highest at 30 min post-injection (0.8±0.25 and 0.64±0.18 %ID/g, respectively). The data of the biodistribution study in the U87-MG xenograft model revealed that these radiotracers could accumulate in the tumor site, and the highest tumor uptake was observed at 60 min post-injection (3.38±0.65 and 3.27±0.5 %ID/g, respectively). The injection of pimozide can block the tumor’s radiotracer uptake, indicating the binding of these radiotracers to the 5-HT7R. The imaging study in the xenograft model also confirms the biodistribution data. The acquired images clearly show the tumor site, and the tumor-to-muscle ratio for 99mTc(CO)3-[6] and 99mTc(CO)3-[7] at 60 min was 3.33 and 3.88, respectively.