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

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© 2016, The Author(s). Purpose: [ 11 C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [ 11 C]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 [ 11 C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain. Methods: A 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). [ 11 C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches. Results: Regional 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 [ 11 C]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. Conclusions: The method proposed for quantification of [ 11 C]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 [ 11 C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.




Yang, K. C., Stepanov, V., Amini, N., Martinsson, S., Takano, A., Nielsen, J., … Finnema, S. J. (2017). Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain. European Journal of Nuclear Medicine and Molecular Imaging, 44(2), 308–320.

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