In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: ¹⁸F-MNI-659 and ¹⁸F-MNI-654

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 ( 18 F-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 ( 18 F-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 ( 18 F-MNI-654 test-retest, 2 men; 18 F-MNI-659 test-retest, 4 men and 1 woman; 18 F-MNI-659 dosimetry, 2 men and 2 women). Brain PET images were acquired over 5.5 h for 18 F-MNI-654 and over 3.5 h for 18 F-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 18 F-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 18 F-MNI-654 kinetics were much slower than 18 F-MNI-659 kinetics. For 18 F-MNI-659, there was good agreement between the Logan and simplified reference tissue models for nondisplaceable binding potential (BP ND ), supporting noninvasive quantification, with test-retest variability less than 10% and intraclass correlation greater than 0.9. The 18 F-MNI-659 effective dose was estimated at 0.024 mSv/MBq. Conclusion: PET imaging in the human brain with 2 novel PDE10A 18 F tracers is being reported. Noninvasive quantification of 18 F-MNI-659 with the simplified reference tissue model using the cerebellum as a reference is possible. In addition, 18 F-MNI-659 kinetics are fast enough for a good estimate of BP ND with 90 min of data, with values around 3.0 in the basal ganglia. Finally, 18 F-MNI-659 dosimetry is favorable and consistent with values reported for other PET radiotracers currently used in humans.

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

“…The TACs of the cerebellum were better described by the 2TCM than the 1TCM, similarly as has been described for several other PDE10A radioligands [10, 11, 14, 16, 18]. Possible explanations for this include a small fraction of specific binding, a kinetically distinguishable nondisplaceable compartment, tissue heterogeneity (gray and white matter), or a contamination from BBB-penetrating radiometabolites [38, 39].…”

“…It is noted that the majority of the studies of PDE10A radioligands did not in detail evaluate the influence of radiometabolites on quantification. For example, only studies using [ 18 F]JNJ-42259152 [16] or [ 18 F]MNI-659 [18] have examined the effect of PET measurement duration on the quantification, and for both radioligands an increase in V T value was obtained with increasing PET measurement duration.…”

Preclinical evaluation of a promising C-11 labeled PET tracer for imaging phosphodiesterase 10A in the brain of living subject

“…Recently, several potent radiotracers targeting PDE10A have been developed and validated in vivo by different groups (Barret et al, 2014; Barret, 2012; Celen et al, 2010; Celen et al, 2013; Harada et al, 2015; Hwang et al, 2014; Kehler et al, 2014; Van Laere et al, 2013a; Van Laere et al, 2013b), including another radiolabeled MP-10 analogue, [ 18 F]JNJ42259152. However, as found with MP-10, the possible influence of a brain-penetrating radioactive metabolite of [ 18 F]JNJ42259152 was reported (Celen et al, 2013; Van Laere et al, 2013b).…”

Functional neuroimaging and chorea: a systematic review

“…(2-(2-(3-(4-(2-[ 18 F]fluoroethoxy)phenyl)- 7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4- isopropoxyisoindoline-1,3-dione) ([ 18 F]MNI-659) is a PET biomarker with specificity for PDE10 [16]. PET studies in early HD patients have demonstrated significantly reduced striatal [ 18 F]MNI-659 compared to healthy controls [17, 18].…”