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

Abstract

Purpose[11C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [11C]Lu AE92686 has high affinity for PDE10A (IC 50 = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [11C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain.MethodsA total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [11C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches.ResultsRegional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V T) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V T values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V T values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while V T values in target regions remained stable. Both pretreatment drugs significantly decreased [11C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP ND) values, derived with the simplified reference tissue model (SRTM), were 13–17 in putamen and 3–5 in substantia nigra and correlated well to values from the Logan plot analysis.ConclusionsThe method proposed for quantification of [11C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [11C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3544-9) contains supplementary material, which is available to authorized users.

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

“…In 2017, Yang et al [ 160 ] reported on the in vivo evaluation of another already known PDE10A-specific radioligand, [ 11 C] LuAE92686 [ 124 , 125 , 126 ] ([ 11 C] 32 , see Figure 6 ), in non-human primates. The suitability of [ 11 C] 32 for PET imaging and quantification of PDE10A in the target region striatum has previously been proven in non-human primates and humans [ 1 , 124 ].…”

“…The suitability of [ 11 C] 32 for PET imaging and quantification of PDE10A in the target region striatum has previously been proven in non-human primates and humans [ 1 , 124 ]. The aim of the current PET study was to further characterize the binding of [ 11 C] 32 to PDE10A regarding specificity and kinetics and to examine whether [ 11 C] 32 is suitable to accurately quantify PDE10A levels in the substantia nigra where this enzyme is exclusively expressed in nerve fibers and terminals [ 101 , 160 ]. The substantia nigra is a key nucleus in relation to the basal ganglia and thus, regional dysfunction of PDE10A is suggested to be associated with the pathophysiology of neuropsychiatric disorders like schizophrenia [ 160 ].…”

“…The aim of the current PET study was to further characterize the binding of [ 11 C] 32 to PDE10A regarding specificity and kinetics and to examine whether [ 11 C] 32 is suitable to accurately quantify PDE10A levels in the substantia nigra where this enzyme is exclusively expressed in nerve fibers and terminals [ 101 , 160 ]. The substantia nigra is a key nucleus in relation to the basal ganglia and thus, regional dysfunction of PDE10A is suggested to be associated with the pathophysiology of neuropsychiatric disorders like schizophrenia [ 160 ]. In that regard, correct quantification of PDE10A in this brain tissue by PET is needed to investigate the effect of altered enzyme density or activity.…”

“…Notably, binding to PDE10A in the substantia nigra has been reported for two other radioligands, [ 18 F] 26 and [ 11 C] 31 ( Figure 6 ), with a BP ND of only 0.4 and 0.5, respectively. Yang et al suggested that this might be caused by lower resolution PET systems in these previous studies [ 160 ]. This assumption is further supported by the fact that the striatal BP ND of [ 11 C] 32 was 85% higher compared to earlier findings in non-human primates due to the use of a high resolution research tomograph (1.6 mm vs. 3.5 mm) and a head fixation device in the present study [ 124 , 160 ].…”

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

“…However, the identified metabolite is not expected to bind to PDE10A and authors of human studies claim this does not impact the quantification of PDE10A with 18 F-JNJ42259152 [130]. 11 C-Lu AE92686 underwent fast metabolism in NHP, with slow increase in cerebellum V T observed throughout the scan, indicating a brain-penetrating metabolite may be present in small quantities [141]. The cerebellum V T increase over time has not yet been reported in human, preventing the assessment of the possibility of brain-penetrating metabolite accumulation.…”