Key result
[11C]MTP38 successfully visualizes PDE7 in vivo with highly specific striatal binding in rats and monkeys.
Why the study?
PDE7 is a potential therapeutic target for neurological and inflammatory diseases, but in vivo visualization of PDE7 had not been successful.
[11C]MTP38 successfully demonstrated in vivo PDE7 imaging in preclinical models, supporting its translation to first-in-human PET studies.
Supports progression to first-in-human PDE7 PET studies; does not yet inform clinical use.
Purpose Phosphodiesterase (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 [ 11 C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7. Methods [ 11 C]MTP38 was radiosynthesized by 11 C-cyanation of a bromo precursor with [ 11 C]HCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with [ 11 C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume ( V T ). The non-displaceable binding potential ( BP ND ) 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 BP ND . Results [ 11 C]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 V T values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm 3 , respectively. The cerebellar V T value was unchanged by pretreatment with unlabeled MTP38. Striatal BP ND 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. Conclusion We have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand. [ 11 C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.
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Obokata et al. (2021) studied Healthy (Preclinical PET ligand evaluation) (n=6). [11C]MTP38 vs. Baseline vs blockade (unlabeled MTP38 or MTP-X) was evaluated on Striatal non-displaceable binding potential (BPND) and total distribution volume (VT). [11C]MTP38 successfully visualized PDE7 in vivo, demonstrating high specific binding in the striatum of rats and monkeys that was dose-dependently reduced by a PDE7 inhibitor.
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