First-in-human study of D6-[18F]FP-(+)-DTBZ, a novel VMAT2 tracer: whole-body biodistribution and brain PET comparison with [18F]FP-(+)-DTBZ (AV-133)

Purpose In the central nerve system type 2 vesicular monoamine transporters (VMAT2) regulate the reuptake of monoamines into pre-synaptic vesicles, playing a critical role in assessing monoamine neuron integrity including Parkinson's disease (PD). This study examined the biodistribution and dosimetry of a novel deuterated VMAT2 radioligand, D6-[ ¹⁸ F]FP-(+)-DTBZ, comparing it head-to-head with its non-deuterated counterpart, [ ¹⁸ F]FP-(+)-DTBZ (AV-133). Methods Six (6) healthy volunteers received intravenous injections of D6-[ ¹⁸ F]FP-(+)-DTBZ (325.9 ± 56.2 MBq) for whole-body PET/CT scans, and radiation-absorbed dose estimates were calculated using PMOD and OLINDA/EXM software. Another six (6) healthy volunteers received D6-[ ¹⁸ F]FP-(+)-DTBZ (370 ± 30 MBq) for a 90-min dynamic brain imaging study, followed by a brain PET scan using [ ¹⁸ F]FP-(+)-DTBZ two weeks later for comparison. Results In this study, D6-[ ¹⁸ F]FP-(+)-DTBZ dosimetry revealed an effective dose of 37.1 ± 7.2 µSv/MBq, with the liver receiving the highest radiation dose (289.6 ± 42.1 µSv/MBq), followed by pancreas (185.2 ± 29.1 µSv/MBq). Brain imaging with D6-[ ¹⁸ F]FP-(+)-DTBZ exhibited a significantly increased uptake in VMAT2-rich regions, particularly the striatum. In a head-to-head comparison between [ ¹⁸ F]FP-DTBZ vs D6-[ ¹⁸ F]FP-(+)-DTBZ, the latter exhibited approximately 15% higher uptake in the caudate, putamen, and nucleus accumbens. Conclusions D6-[ ¹⁸ F]FP-(+)-DTBZ is a safe and improved VAMT2 specific imaging agent, which may be suitable for assisting the diagnosis of PD by evaluating changes of VMAT2 binding of monoamine neurons in the brain.