O. Barret, D. Thomae, A. Tavares
Aug 1, 2014
Citations
3
Influential Citations
59
Citations
Quality indicators
Journal
The Journal of Nuclear Medicine
Abstract
Phosphodiesterase (PDE) 10A is an enzyme involved in the regulation of cyclic adenosine monophosphate and cyclic guanosine monophosphate and is highly expressed in medium-sized spiny neurons of the striatum, making it an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function. Potential ligands for PET imaging of PDE10A have been reported. Here, we report the first-in-human characterization of 2 new PDE10A radioligands, 2-(2-(3-(1-(2-fluoroethyl)-1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione (18F-MNI-654) and 2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione (18F-MNI-659), with the goal of selecting the best one for use in future studies interrogating pathophysiologic changes in neuropsychiatric disorders and aiding pharmaceutical development targeting PDE10A. Methods: Eleven healthy volunteers participated in this study (18F-MNI-654 test–retest, 2 men; 18F-MNI-659 test–retest, 4 men and 1 woman; 18F-MNI-659 dosimetry, 2 men and 2 women). Brain PET images were acquired over 5.5 h for 18F-MNI-654 and over 3.5 h for 18F-MNI-659, and pharmacokinetic modeling with plasma- and reference-region (cerebellar cortex)-based methods was performed. Whole-body PET images were acquired over 6 h for 18F-MNI-659 and radiation dosimetry estimated with OLINDA. Results: Both radiotracers were similarly metabolized, with about 20% of intact parent remaining at 120 min after injection. PET time–activity data demonstrated that 18F-MNI-654 kinetics were much slower than 18F-MNI-659 kinetics. For 18F-MNI-659, there was good agreement between the Logan and simplified reference tissue models for nondisplaceable binding potential (BPND), supporting noninvasive quantification, with test–retest variability less than 10% and intraclass correlation greater than 0.9. The 18F-MNI-659 effective dose was estimated at 0.024 mSv/MBq. Conclusion: PET imaging in the human brain with 2 novel PDE10A 18F tracers is being reported. Noninvasive quantification of 18F-MNI-659 with the simplified reference tissue model using the cerebellum as a reference is possible. In addition, 18F-MNI-659 kinetics are fast enough for a good estimate of BPND with 90 min of data, with values around 3.0 in the basal ganglia. Finally, 18F-MNI-659 dosimetry is favorable and consistent with values reported for other PET radiotracers currently used in humans.