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 (IC50 = 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 (VT) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar VT values could not be derived by the 2TCM. For cerebellum, a proposed reference region, VT values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while VT 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 (BPND) 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.
Highlights
Phosphodiesterase 10A (PDE10A) is a member of the cyclic nucleotide phosphodiesterase family and modulates intracellular signal transduction by catabolizing cyclic adenosine monophosphate and guanosine monophosphate [1]
The method proposed for quantification of [11C]Lu AE92686 binding in applied studies in nonhuman primates (NHP) is based on 63 min positron emission tomography (PET) data and simplified reference tissue model (SRTM) with cerebellum as a reference region
The study supports that [11C]Lu AE92686 can be used for PET examinations of PDE10A binding in substantia nigra
Summary
Phosphodiesterase 10A (PDE10A) is a member of the cyclic nucleotide phosphodiesterase family and modulates intracellular signal transduction by catabolizing cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) [1]. Numerous potential radioligands for imaging of PDE10A binding by positron emission tomography (PET) have been suggested and several have been examined in nonhuman primates (NHP) or in humans [8,9,10,11,12,13,14,15,16,17,18,19] Most of these radioligands provide adequate target-to-background signal for the striatum and GP, but so far, radioligand binding in the SN has been examined only for [18F]JNJ-42259152 or [11C]IMA107. Both studies report binding potential (BPND) values of approximately 0.5 for SN in healthy human subjects with corresponding striatal BPND values of 3.5 or 2.2, respectively [8, 16]. Considering that the SN is a key nucleus in relation to the basal ganglia [21], and that regional differences in PDE10A functioning may be a part of the pathophysiology of neuropsychiatric disorders [2, 5, 6], it is important to develop a PET methodology enabling quantification of PDE10A binding in the SN of the primate brain
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