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

Manabu Kubota,Tatsuya Kikuchi,Makoto Higuchi,Kazunori Kawamura,Ming-Rong Zhang,Keisuke Takahata,Kenji Tagai,Yasunori Sano,Yasuyuki Kimura,Yasuharu Yamamoto,Maki Okada,Kiwamu Matsuoka,Yuhei Takado,Hitoshi Shimada,Masanori Ichise,Chie Seki

doi:10.1007/s00259-021-05235-0

Abstract

PurposePhosphodiesterase 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.MethodsSeven 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.ResultsPET 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.ConclusionWe 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.

Highlights

Cyclic nucleotide phosphodiesterases (PDEs) are 11 genetically related families of phosphohydrolases (PDE1-PDE11)
Plasma analysis indicated that the metabolic conversion of 11C-MTP38 is relatively slow, resulting in high uptake of intact radioligand into the brain
Its uptake was high in brain regions, including the pallidum, putamen, caudate, pons, and thalamus, where abundant Phosphodiesterase 7 (PDE7) expression has been reported

Summary

Introduction

Cyclic nucleotide phosphodiesterases (PDEs) are 11 genetically related families of phosphohydrolases (PDE1-PDE11). Among PDEs, the PDE7 family selectively hydrolyses cAMP, and comprises two genes, PDE7A and PDE7B. PDE7A is widely expressed in the brain and peripheral organs, while PDE7B is primarily distributed in the brain, including the striatum, thalamus, and hippocampus [4,5,6,7]. Several preclinical studies have suggested the significance of PDE7 as a novel therapeutic target for neuropsychiatric diseases, including Parkinson’s disease [9], Alzheimer’s disease [10], and addiction [11]. Another study reported that inhibition of PDE7 reversed memory impairments caused by amyloid-beta depositions in the hippocampus and neocortex, and improved hippocampal neurogenesis in a mouse model of Alzheimer’s disease [10]. Developing methods for visualizing and quantifying PDE7 in human brain would be helpful for etiological assays and therapeutic evaluations of these conditions

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