Development of a novel radioligand for imaging 18-kD translocator protein (TSPO) in a rat model of Parkinson's disease

PURPOSE: The inflammation reaction in the brain may stimulate damage repair or possibly lead to secondary brain injury. It is often associated with activated microglia, which would overexpress 18-kDa translocator protein (TSPO). In this study, we successfully developed a new TSPO radioligand, [(18)F]-2-(4-fluoro-2-(p-tolyloxy)phenyl)-1,2-dihydroisoquinolin-3(4H)-one ([(18)F]FTPQ), and evaluate its potential to noninvasively detect brain changes in a rat model of Parkinson's disease (PD). PROCEDURES: The precursor (8) for [(18)F]FTPQ preparation was synthesized via six steps. Radiofluorination was carried out in the presence of a copper catalyst, and the crude product was purified by high-performance liquid chromatography (HPLC) to give the desired [(18)F]FTPQ. The rat model of PD was established by the injection of 6-OHDA into the right hemisphere of male 8-week-old Sprague-Dawley rats. MicroPET/CT imaging and immunohistochemistry (IHC) were performed to characterize the biological properties of [(18)F]FTPQ. RESULTS: The overall chemical yield for the precursor (8) was around 14% after multi-step synthesis. The radiofluorination efficiency of [(18)F]FTPQ was 60 ± 5%. After HPLC purification, the radiochemical purity was higher than 98%. The overall radiochemical yield was approximately 19%. The microPET/CT images demonstrated apparent striatum accumulation in the brains of PD rats at the first 30 min after intravenous injection of [(18)F]FTPQ. Besides, longitudinal imaging found the uptake of [(18)F]FTPQ in the brain may reflect the severity of PD. The radioactivity accumulated in the ipsilateral hemisphere of PD rats at 1, 2, and 3 weeks after 6-OHDA administration was 1.84 ± 0.26, 3.43 ± 0.45, and 5.58 ± 0.72%ID/mL, respectively. IHC revealed that an accumulation of microglia/macrophages and astrocytes in the 6-OHDA-injected hemisphere. CONCLUSIONS: In this study, we have successfully synthesized [(18)F]FTPQ with acceptable radiochemical yield and demonstrated the feasibility of [(18)F]FTPQ as a TSPO radioligand for the noninvasive monitoring the disease progression of PD.