Dataset Information

Characterization of [¹¹C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain.

ABSTRACT:

Purpose

[¹¹C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [¹¹C]Lu AE92686 has high affinity for PDE10A (IC ₅₀?=?0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [¹¹C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain.

Methods

A total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [¹¹C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches.

Results

Regional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V _T) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V _T values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V _T values increased by ?30 % with increasing PET measurement duration from 63 to 123 min, while V _T values in target regions remained stable. Both pretreatment drugs significantly decreased [¹¹C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP _ND) values, derived with the simplified reference tissue model (SRTM), were 13-17 in putamen and 3-5 in substantia nigra and correlated well to values from the Logan plot analysis.

Conclusions

The method proposed for quantification of [¹¹C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [¹¹C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.

SUBMITTER: Yang KC

PROVIDER: S-EPMC5215309 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain.

Yang Kai-Chun KC Stepanov Vladimir V Amini Nahid N Martinsson Stefan S Takano Akihiro A Nielsen Jacob J Bundgaard Christoffer C Bang-Andersen Benny B Grimwood Sarah S Halldin Christer C Farde Lars L Finnema Sjoerd J SJ

European journal of nuclear medicine and molecular imaging 20161105 2

<h4>Purpose</h4>[11C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [11C]Lu AE92686 has high affinity for PDE10A (IC 50 = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [11C]Lu AE92686 binding to PDE10A in the nonhuman primate (N ...[more]

PMID: 27817159

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Project description:Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling. A PET tracer for PDE10A may serve as a tool to evaluate PDE10A expression in vivo in central nervous system disorders with striatal pathology. Here, we further characterized the binding properties of a previously reported radioligand we developed for PDE10A, [(11)C]TZ1964B, in rodents and nonhuman primates (NHPs). The tritiated counterpart [(3)H]TZ1964B was used for in vitro binding characterizations in rat striatum homogenates and in vitro autoradiographic studies in rat brain slices. The carbon-11 labeled [(11)C]TZ1964B was utilized in the ex vivo autoradiography studies for the brain of rats and microPET imaging studies for the brain of NHPs. MicroPET scans of [(11)C]TZ1964B in NHPs were conducted at baseline, as well as with using a selective PDE10A inhibitor MP-10 for either pretreatment or displacement. The in vivo regional target occupancy (Occ) was obtained by pretreating with different doses of MP-10 (0.05-2.00 mg/kg). Both in vitro binding assays and in vitro autoradiographic studies revealed a nanomolar binding affinity of [(3)H]TZ1964B to the rat striatum. The striatal binding of [(3)H]TZ1964B and [(11)C]TZ1964B was either displaced or blocked by MP-10 in rats and NHPs. Autoradiography and microPET imaging confirmed that the specific binding of the radioligand was found in the striatum but not in the cerebellum. Blocking studies also confirmed the suitability of the cerebellum as an appropriate reference region. The binding potentials (BPND) of [(11)C]TZ1964B in the NHP striatum that were calculated using either the Logan reference model (LoganREF, 3.96 ± 0.17) or the simplified reference tissue model (SRTM, 4.64 ± 0.47), with the cerebellum as the reference region, was high and had good reproducibility. The occupancy studies indicated a MP-10 dose of 0.31 ± 0.09 mg/kg (LoganREF)/0.45 ± 0.17mg/kg (SRTM) occupies 50% striatal PDE10A binding sites. Studies in rats and NHPs demonstrated radiolabeled TZ1964B has a high binding affinity and good specificity for PDE10A, as well as favorable in vivo pharmacokinetic properties and binding profiles. Our data suggests that [(11)C]TZ1964B is a promising radioligand for in vivo imaging PDE10A in the brain of living subject.

Project description: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.