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Abstract
PurposeThe 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, [18F]-2-(4-fluoro-2-(p-tolyloxy)phenyl)-1,2-dihydroisoquinolin-3(4H)-one ([18F]FTPQ), and evaluate its potential to noninvasively detect brain changes in a rat model of Parkinson’s disease (PD).ProceduresThe precursor (8) for [18F]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 [18F]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 [18F]FTPQ.ResultsThe overall chemical yield for the precursor (8) was around 14% after multi-step synthesis. The radiofluorination efficiency of [18F]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 [18F]FTPQ. Besides, longitudinal imaging found the uptake of [18F]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.ConclusionsIn this study, we have successfully synthesized [18F]FTPQ with acceptable radiochemical yield and demonstrated the feasibility of [18F]FTPQ as a TSPO radioligand for the noninvasive monitoring the disease progression of PD.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by impaired dopamine or norepinephrine production, and by the formation of alpha-synuclein
After high-performance liquid chromatography (HPLC) purification, the radiochemical purity was higher than 98%
Longitudinal imaging found the uptake of [18F]FTPQ in the brain may reflect the severity of PD
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by impaired dopamine or norepinephrine production, and by the formation of alpha-synuclein. The real cause of PD remains poorly understood, it is regarded that chronic neuroinflammation plays a vital role for this disease, supported by evidence from activated microglia in the substantia nigra of postmortem brain samples [1, 2] and inflammatory cytokines [3]. The activity of microglia in a healthy brain is only at a basal level, but it would be upregulated in response to various CNS damages. A significantly elevated expression of TSPO has been observed upon the transition of microglia from a normal condition to the activated stage [6]. The glial proliferation may be the reason for the upregulation of TSPO, which can possibly increase neurosteroid synthesis to provide protective activity at injury sites [7].
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