Abstract
PurposePhosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7.Methods[11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND.Results[11C]MTP38 was synthesized with radiochemical purity ≥99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function.ConclusionWe have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.
Highlights
Phosphodiesterases (PDEs) are a group of enzymes regulating intracellular levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate
While PDE7A is widely expressed in the brain and peripheral organs [4, 5], PDE7B is abundantly expressed in the brain, in the striatum, nucleus accumbens, olfactory tubercle, thalamus, and hippocampus [5,6,7]
MTP38 potently exerted inhibitory effects on PDE7A and PDE7B with IC50 values of 9.81 (95% confidence interval (CI): 4.45–15.5), 1.21, respectively, while its IC50 for PDE2A, 4B1, and 10A2 exceeded 100 nM (Table 1)
Summary
Phosphodiesterases (PDEs) are a group of enzymes regulating intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). These second messengers stimulate intracellular signaling pathways that lead to the activation of protein kinases, resulting in cellular responses in fundamental physiological processes such as neural, cardiovascular, immune, visceromotor, and reproductive functions. PDE7 is composed of PDE7A and PDE7B, both of which hydrolyze cAMP [1,2,3]. An increase in intracellular cAMP by PDE7 inhibitors is a potential mechanism of therapeutic approaches to neurological and inflammatory diseases [8]. Previous studies have demonstrated pharmacologic activities of PDE7-targeting drug candidates in rodent models of Parkinson’s disease [9], Alzheimer’s disease [10], addiction [11], and multiple sclerosis [12]
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