24 research outputs found

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

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    We have developed 8-amino-3-(2S,5R-dimethyl-1-piperidyl)-[1,2,4]triazolo[4,3-a]pyrazine-5-[11C]carbonitrile ([11C]MTP38) as a PET tracer for the imaging of phosphodiesterase 7. For the fully automated production of [11C]MTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of [11C]MTP38 using [11C]hydrogen cyanide ([11C]HCN) as a PET radiopharmaceutical. Radiosynthesis of [11C]MTP38 was performed using an automated 11C-labeling synthesizer developed in-house within 40 min after the end of irradiation. [11C]MTP38 was obtained with a relatively high radiochemical yield (33 ± 5.5% based on [11C]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 [11C]MTP38 injection complied with our in-house QC and quality assurance specifications. We successfully automated the radiosynthesis of [11C]MTP38 for clinical applications using an 11C-labeling synthesizer and sterile isolator. Taken together, this protocol provides a new radiopharmaceutical [11C]MTP38 suitable for clinical applications

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

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    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

    APPLICATION OF SMALL ANIMAL POSITRON EMISSION TOMOGRAPHIC IMAGING TO PRECLINICAL ASSESSMENT OF DRUGS ACTING ON SEROTONIN TRANSPORTER

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    We investigated the comparability of pharmacodynamic parameters for the occupancy of serotonin transporter (5-HTT) by therapeutic agents in rat positron emission tomographic (PET) studies with our predetermined data from ex vivo animal experiments and clinical PET scans, in order to examine the utility of high-resolution PET imaging system for preclinical characterization of 5-HTT inhibitors. Rats were treated with varying doses of high-affinity inhibitors of 5-HTT, including fluvoxamine and a newly developed compound, Wf-516, and subsequently underwent PET scans with [11C] 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([11C]DASB). PET images indicated a reduction of [11C]DASB binding to 5-HTT as a function of the administered doses and/or plasma concentrations of fluvoxamine and Wf-516, and the ED50 estimates of these drugs were in general agreement with those estimated by our previous ex vivo measurements in rats. Moreover, the EC50 value of fluvoxamine in plasma determined here (6.1 ng/mL) was nearly equivalent to the value determined in human PET studies (4.6 ng/mL). These findings support the view that the use of small animal PET facilitates a quantitative comparison of in-development drugs targeting 5-HTT with known inhibitors and a predictive estimation of their doses exerting therapeutic effects in humans.第23回日本薬物動態学

    Strategies for utilizing neuroimaging biomarkers in CNS drug discovery and development: CINP/JSNP working group report.

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    Despite large unmet medical needs in the field for several decades, central nervous system (CNS) drug discovery and development has been largely unsuccessful. Biomarkers, particularly those utilizing neuroimaging, have played important roles in aiding CNS drug development, including dosing determination of investigational new drugs (INDs). The utility of biomarkers as tools to overcome issues of CNS drug development is the subject for this review.In this review aimed at employing biomarkers as tools to overcome issues surrounding CNS drug development, we first analyzed problems in utilizing biomarkers in processes of drug discovery and development for CNS disorders. Based on this analysis, we propose a new paradigm containing five distinct tiers to further clarify the use of biomarkers and establish new strategies for decision-making in the context of clinical drug development. Specifically, we discuss more rational ways to determine optimal dose for INDs with novel mechanisms and targets, and propose additional categorization criteria to further the use of biomarkers in patient stratification and efficacy prediction. Finally, we propose validation and development of new neuroimaging biomarkers through Public-Private-Partnerships to realize rational and successful drug discovery and development for CNS disorders

    Quantification of central substance P receptor occupancy by aprepitant using small animal positron emission tomography.

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    Central substance P receptors, termed NK-1 receptors, have been considered as therapeutic targets in the development of drugs against diverse conditions including emesis, overactive bladder and depression. Here, we applied small animal positron emission tomography (PET) and a radioligand for NK-1 receptors, [18F]FE-SPA-RQ, for measuring occupancies of these receptors by a selective antagonist, aprepitant, in order to examined the validity of this in vivo imaging system for preclinical characterization of candidate agents acting on NK-1 receptors, and as a tool for predicting optimal doses in humans. PET in gerbils depicted high uptake in the striatum and dose-dependent displacement with increasing dose of aprepitant. Occupancies increased as a function of aprepitant plasma concentrations according to a one-site competition model, in good agreement with reported occupancy-concentration relationships in clinical studies after correction for species differences in plasma protein-unbound aprepitant fractions. These occupancy data were further supported by ex vivo autoradiography of brain samples from aprepitant-treated gerbils. In a pilot study of a marmoset, we obtained more accurate determinations of NK-1 receptor occupancy, less affected by spillover of signals from extracranial tissues than in gerbil experiments. These findings support the utility of small animals and quantitative PET in the development of drugs targeting NK-1 receptors

    Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain.

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    A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT(1A)) receptor, called Wf-516 (structural formula: (2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT(1A) receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT(1A) receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT(1A) receptors. In addition, [(35)S]guanosine 5'-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT(1A) receptors. This finding has lent support to reports that diverse partial agonists for 5-HT(1A) receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants

    Presynaptic Selectivity of a Ligand for Serotonin 1A Receptors Revealed by In Vivo PET Assays of Rat Brain

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    A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT1A) receptor, called Wf-516 (structural formula:(2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4 oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT1A receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT1A receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT1A receptors. In addition, [35S]guanosine 5\u27-O-[-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT1A receptors. This finding haslent support to reports that diverse partial agonists for 5-HT1A receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants

    Utility of small-animal positron emission tomographic imaging of rats for preclinical development of drugs acting on serotonin transporter

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    Visualization of neurotransmission components in living small animals using positron emission tomography(PET) has the potential of contributing to the preclinical development of neuroactive drugs, although it is yet to be examined whether quantitative animal PET data on candidate compounds can be extrapolated to humans. Here, we investigated the comparability of the occupancies of serotonin transporter (5-HTT) by therapeutic agents in rat PET studies with our predetermined data from ex- vivo animal experiments and clinical PET scans. Rats were treated with varying doses of fluvoxamine and a newly developed compound, (2S)-1-[4-(3,4-dichlorophenyl) piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)-benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride (Wf-516), and underwent PET scans with [11C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([11C]DASB), a selective radioligand for in-vivo quantification of 5-HTT. PET images indicated a reduction of [11C]DASB binding to 5-HTT as a function of the doses and/or plasma concentrations of fluvoxamine and Wf-516. The doses of these drugs at half-maximal effect (15.2 mg/kg and 3.1 mg/kg, respectively), determined that using binding potentials for [11C]DASB, were comparable to those estimated by our previous ex-vivo measurements in rats (4.5 mg/kg and 1.1 mg/kg, respectively), as there was only a 3-fold difference between these results. Moreover, the plasma concentration of fluvoxamine needed for 50% occupancy of central 5-HTT (6.1 ng/ml) was almost equivalent to the value determined in human PET studies (4.6 ng/ml). These findings support the view that the conjunctive use of small-animal PET and [11C]DASB facilitates a quantitative comparison of indevelopment drugs targeting 5-HTT with established inhibitors and a predictive estimation of their plasma concentrations exerting therapeutic effects in humans
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