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, while 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 the 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, VT values estimated 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 the 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 to evaluate PDE7 in the brain and is currently applied to a first-in-human PET study.

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

“…Brain clearance was slightly slower in rhesus monkeys than in rats but, generally, a fast washout was observed. After pre-treatment with 25 or MTP-X , the striatal activity levels in rats and rhesus monkeys were significantly decreased demonstrating high PDE7-specific binding of [ 11 C] 25 in vivo consistent with the in vitro results [ 99 ]. Metabolite analysis revealed moderate in vivo stability of [ 11 C] 25 in monkeys with 27% of intact radioligand in plasma at 90 min p.i.…”

“…Metabolite analysis revealed moderate in vivo stability of [ 11 C] 25 in monkeys with 27% of intact radioligand in plasma at 90 min p.i. while one major and more polar radiometabolite was detected [ 99 ]. Striatal PDE7 occupancies of 53% and 87% at 30 mg/kg of MTP-X have been estimated in two monkeys, respectively [ 99 ].…”

“…while one major and more polar radiometabolite was detected [ 99 ]. Striatal PDE7 occupancies of 53% and 87% at 30 mg/kg of MTP-X have been estimated in two monkeys, respectively [ 99 ]. Based on these promising pre-clinical results, Obokata et al suggest [ 11 C] 25 to be an appropriate radioligand for in vivo investigation of the PDE7 enzyme in the brain [ 99 ].…”

“… Molecular structures and IC 50 or EC 50 values for the PDE7 isoforms of ([ 18 F]) 22 and ([ 11 C]) 23 [ 96 , 97 ], ([ 3 H]) 24 [ 98 ], and ([ 11 C]) 25 [ 99 ]. …”

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

“…We recently developed 11 C-MTP38 (8-amino-3-(2S*,5R*dimethyl-1-piperidyl)- [1,2,4]triazolo [4,3-a]pyrazine- 11 C-5carbonitrile), a radiolabeled compound that has high affinity and selectivity for PDE7. MTP38 acts on PDE7A and PDE7B with half-maximal inhibitory concentration (IC 50 ) values of 9.81 nM and 1.21 nM, respectively, and thus is more selective for PDE7B than for PDE7A [14]. In addition, it is much less reactive with other PDEs with IC 50 exceeding 100 nM [14].…”