Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain

Abstract

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 [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. Conclusion We 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.

Automated radiosynthesis of [11C]MTP38—a phosphodiesterase 7 imaging tracer—using [11C]hydrogen cyanide for clinical applications

“…We recently developed 11 C‐labeled MTP38 ([ 11 C]MTP38) as a positron emission tomography (PET) tracer for the imaging of PDE7 (Figure 1). 1 In rat and monkey PET measurements, pre‐administration of unlabeled MTP38 blocked radioactivity uptake in the brain, supporting the saturable binding of [ 11 C]MTP38 1 . In a first‐in‐human PET study of [ 11 C]MTP38, PET results showed relatively high retentions in several brain regions, including the striatum, globus pallidus, and thalamus, and rapid washout from the cerebellar cortex, corroborating the known distribution of PDE7 2 .…”

“…Herein, 8‐amino‐3‐(2 S ,5 R ‐dimethyl‐1‐piperidyl)‐[1,2,4]triazolo[4,3‐ a ]pyrazine‐5‐carbonitrile (MTP38) was developed as a phosphodiesterase 7 (PDE7) ligand by Mitsubishi Tanabe Pharma Corporation (Osaka, Japan) and Ube Industries, Ltd (Tokyo, Japan). MTP38 potently exerted inhibitory effects on PDE7A and PDE7B with IC 50 values (nM) of 9.81 and 1.21, respectively, and showed selective affinity for other PDEs (IC 50 > 100 nM) 1 . We recently developed 11 C‐labeled MTP38 ([ 11 C]MTP38) as a positron emission tomography (PET) tracer for the imaging of PDE7 (Figure 1).…”

“…[ 11 C]MTP38 was synthesized using [ 11 C]hydrogen cyanide ([ 11 C]HCN) from [ 11 C]CO 2 , which was generated by the 14 N(p,α) 11 C nuclear reaction using a cyclotron 1 . [ 11 C]HCN is a useful radioactive agent for synthesizing 11 C‐labeling PET imaging tracers 3–7 .…”

“…We have developed 8-amino-3-(2S,5R-dimethyl-1-piperidyl)- [1,2,4]triazolo [4,3-a] based on [ 11 C]CO 2 at the end of irradiation, decay-corrected, n = 15), radiochemical purity (>97%, n = 15), and molar activity (47 ± 12 GBq/μmol at the end of synthesis, n = 15). All the results of the quality control (QC) testing for the [ 11 C]MTP38 injection complied with our in-house QC and quality assurance specifications.…”

“…Taken together, this protocol provides a new radiopharmaceutical (IC 50 > 100 nM). 1 We recently developed 11 C-labeled MTP38 ([ 11 C]MTP38) as a positron emission tomography (PET) tracer for the imaging of PDE7 (Figure 1). 1 In rat and monkey PET measurements, pre-administration of unlabeled MTP38 blocked radioactivity uptake in the brain, supporting the saturable binding of [ 11 C]MTP38.…”