Abstract
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 [11C]DTBZ and [18F]FP-DTBZ have been used to assess the degree of nigrostriatal deficit in Parkinson’s disease (PD) using positron emission tomography (PET). [18F]FE-DTBZ-d4, the nondeuterated analogue of [18F]FE-DTBZ showed similar imaging properties with better stability against defluorination. Therefore, [18F]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 [18F]FE-DTBZ-d4 in nonhuman primates (NHPs), with comparison to [11C]DTBZ and [18F]FE-DTBZ. Radiolabeling was successfully achieved either by one-step 11C-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 [18F]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. [18F]FE-DTBZ-d4 (SUV: 4.28 ± 1.01) displayed higher brain uptake compared to both [18F]FE-DTBZ (SUV: 3.43 ± 0.54) and [11C]DTBZ (SUV: 3.06 ± 0.32) and faster washout. Binding potential (BPND) values of [18F]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 [11C]DTBZ and [18F]FE-DTBZ. [18F]FE-DTBZ showed faster radiometabolism in plasma compared to [11C]DTBZ and [18F]FE-DTBZ-d4. [18F]FE-DTBZ-d4 is a suitable radioligand for quantification of VMAT2 in the nonhuman primate brain, with better imaging properties than [11C]DTBZ and [18F]FE-DTBZ. A preliminary comparison suggests that [18F]FE-DTBZ-d4 has increased stability against defluorination compared to the nondeuterated analogue.
Highlights
The vesicular monoamine transporter 2 (VMAT2) is an integral membrane protein, previously known as the synaptic vesicular monoamine transporter, mainly present in neuronal cells of the central, peripheral, and enteric nervous system.[1]
VMAT2 is required for the vesicular release of the neurotransmitter gamma-aminobutyric acid (GABA) in nigrostriatal and mesolimbic dopamine neurons.[3]
Previous studies have reported that the dysfunction of VMAT2 can evoke cytoplasmic dopamine accumulation, which leads to dopaminergic neuron death.[6]
Summary
The vesicular monoamine transporter 2 (VMAT2) is an integral membrane protein, previously known as the synaptic vesicular monoamine transporter, mainly present in neuronal cells of the central, peripheral, and enteric nervous system.[1] VMAT2 transports monoamines such as dopamine, norepinephrine, serotonin, and histamine from cellular cytosol into synaptic vesicles.[2] VMAT2 is required for the vesicular release of the neurotransmitter gamma-aminobutyric acid (GABA) in nigrostriatal and mesolimbic dopamine neurons.[3]. The degeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNc) in PD leads to the loss of nigrostriatal terminals and to the reduction of dopamine levels in the striatum.[4,5] There are several evidence that link VMAT2 to dopaminergic cell loss in PD. Other studies have shown that protein expression levels of VMAT2 were significantly reduced in PD patients[7] and that an increased VMAT2 level or function might protect against the development of PD.[8,9] striatal VMAT2 is considered as a presynaptic marker of dopamine terminal loss in PD.[10]
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