A first-in-human study of 11C-MTP38, a novel PET ligand for phosphodiesterase 7

Abstract

Purpose Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand 11C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains. Methods Seven healthy males underwent a 90-min PET scan after injection of 11C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes (VTs) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTMO) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference. Results PET images with 11C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. VT values were robustly estimated by two-tissue compartment model analysis (mean VT = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of 11C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTMO and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTMO and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of 11C-MTP38-PET. Conclusion We have provided the first demonstration of PET visualization of PDE7 in human brains. 11C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.

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

“…The activity in the non-target region cerebellar cortex decreased rapidly while a slow washout from PDE7-rich brain areas like pallidum and putamen was observed indicating specific binding of the radioligand. The highest V T and non-displaceable binding potential (BP ND ) values of [ 11 C]25 were assessed in the pallidum (4.2 and 0.55) and the putamen (3.9 and 0.46) followed by pons, thalamus and caudate nucleus, which is consistent with the known distribution pattern of PDE7 in the brain [100]. However, some activity accumulation was detected in the cerebral white matter as previously shown in rats and rhesus monkeys [99,100].…”

“…The highest V T and non-displaceable binding potential (BP ND ) values of [ 11 C]25 were assessed in the pallidum (4.2 and 0.55) and the putamen (3.9 and 0.46) followed by pons, thalamus and caudate nucleus, which is consistent with the known distribution pattern of PDE7 in the brain [100]. However, some activity accumulation was detected in the cerebral white matter as previously shown in rats and rhesus monkeys [99,100]. In these pre-clinical studies, the activity uptake in the cerebellum could not be reduced in blocking experiments and thus, the authors suggested that this might reflect non-specific binding of [ 11 C]25 rather than possible accumulation of brain-penetrating radiometabolites [100].…”

“…In these pre-clinical studies, the activity uptake in the cerebellum could not be reduced in blocking experiments and thus, the authors suggested that this might reflect non-specific binding of [ 11 C]25 rather than possible accumulation of brain-penetrating radiometabolites [100]. This assumption is further supported by the low inter-subject variability and the high time-stability of the estimated [ 11 C]25 V T values in all brain regions over 60-80 min scan duration [100]. Metabolite analysis revealed around 50% of intact [ 11 C]25 in plasma at 90 min p.i.…”

“…Very recently, the first-in-human PET study using [ 11 C]25 has been published by Kubota et al [100]. PET scans in seven healthy volunteers displayed a high initial brain uptake of [ 11 C]25 with peak SUV values between 4 and 8 [100].…”

“…Very recently, the first-in-human PET study using [ 11 C]25 has been published by Kubota et al [100]. PET scans in seven healthy volunteers displayed a high initial brain uptake of [ 11 C]25 with peak SUV values between 4 and 8 [100]. The activity in the non-target region cerebellar cortex decreased rapidly while a slow washout from PDE7-rich brain areas like pallidum and putamen was observed indicating specific binding of the radioligand.…”