PET Imaging of VMAT2 with the Novel Radioligand [F]FE-DTBZ-d4 in Nonhuman Primates: Comparison with [C]DTBZ and [F]FE-DTBZ.

The vesicular monoamine transporter type 2 (VMAT2) is believed to be responsible for the uptake of monoamines into the vesicles of the synaptic terminals. Two VMAT2 radioligands [C]DTBZ and [F]FP-DTBZ have been used to assess the degree of nigrostriatal deficit in Parkinson's disease (PD) using positron emission tomography (PET). [F]FE-DTBZ-d4, the nondeuterated analogue of [F]FE-DTBZ showed similar imaging properties with better stability against defluorination. Therefore, [F]FE-DTBZ-d4 draws attention to be investigated as an imaging marker for VMAT2 in the brain. The aim of this study was to investigate the brain kinetics and quantification of [F]FE-DTBZ-d4 in nonhuman primates (NHPs), with comparison to [C]DTBZ and [F]FE-DTBZ. Radiolabeling was successfully achieved either by one-step C-methylation or by a two-step fluorine-18 nucleophilic substitution reaction. The stability and radiochemical yield were analyzed with high-performance liquid chromatography (HPLC). Three female cynomolgus monkeys were included in the study and underwent a total of 12 positron emission tomography (PET) measurements. Each monkey was examined with each tracer. In addition, two pretreatment and one displacement PET measurements with tetrabenazine (2.0 mg/kg) were performed for [F]FE-DTBZ-d4. All PET measurements were conducted using a high-resolution research tomograph (HRRT) system. Radiometabolites were measured in monkey plasma using gradient radio-HPLC. [F]FE-DTBZ-d4 (SUV: 4.28 ± 1.01) displayed higher brain uptake compared to both [F]FE-DTBZ (SUV: 3.43 ± 0.54) and [C]DTBZ (SUV: 3.06 ± 0.32) and faster washout. Binding potential (BP) values of [F]FE-DTBZ-d4 in different brain regions (putamen: 5.5 ± 1.4; caudate: 4.4 ± 1.1; midbrain: 1.4 ± 0.4) were higher than those of [C]DTBZ and [F]FE-DTBZ. [F]FE-DTBZ showed faster radiometabolism in plasma compared to [C]DTBZ and [F]FE-DTBZ-d4. [F]FE-DTBZ-d4 is a suitable radioligand for quantification of VMAT2 in the nonhuman primate brain, with better imaging properties than [C]DTBZ and [F]FE-DTBZ. A preliminary comparison suggests that [F]FE-DTBZ-d4 has increased stability against defluorination compared to the nondeuterated analogue.