Discovery and Development of ¹¹C-Lu AE92686 as a Radioligand for PET Imaging of Phosphodiesterase10A in the Brain

Abstract

Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-11 C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo [1,5-a]pyridine ( 11 C-Lu AE92686) and its tritiated analog 3 H-Lu AE92686. Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and 11 C-labeled compounds were synthesized. 3 H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and 11 C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: 11 C-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3 H-Lu AE92686. The binding of 11 C-Lu AE92686 and 3 H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BP ND ) of 11 C-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BP ND was found to be high and reproducible-that is, BP ND s were 6.5 ± 0.3 (n 5 3) and 7.5 ± 1.0 (n 5 12) in monkeys and humans, respectively. Conclusion: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that 11 C-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.Key Words: 11 C; 3 H; PET; PDE10A; brain imaging; Lu AE92686 J Nucl Med 2014; 55:1513 55: -1518 55: DOI: 10.2967 Phosphodi esterase 10A (PDE10A) is predominantly expressed in medium spiny neurons and plays a key role in striatal signaling. During the past 10 y, large efforts have been made to develop PDE10A inhibitors for the treatment of schizophrenia (1-3). Preclinical evidence in several animal models suggests that PDE10A inhibitors can improve positive, negative, and cognitive symptoms of schizophrenia, and current clinical trials evaluate PDE10A inhibitors for the treatment of schizophrenia (4). Noninvasive imaging techniques such as PET may be useful for the clinical development of PDE10A inhibitors, because they may provide comparative data on the expression of the enzyme in healthy individuals and in individuals with brain disorders. Furthermore, a PDE10A PET ligand can be used to provide evidence that a clinical drug candidate reaches and bind...

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

“…Positron emission tomography (PET) imaging is widely used to assess target occupancy and to establish a correlation between occupancy and efficacy, which helps to select dosage in the clinic and helps to interpret clinical outcomes (Passchier et al, 2002;Wong and Pomper, 2003). To this end, several PDE10A PET tracers have been developed by us and others, including [ (Celen et al, 2010) (Kehler et al, 2014) (Barret et al, 2014), and [ (Plisson et al, 2014). In the current study, we identified and characterized AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel PDE10A antagonist tracer with a distinct chemical structure compared with previously published tracers, which exhibits desirable tracer profiles, such as subnanomolar PDE10A binding affinity, optimal in vitro and in vivo kinetic properties, and selective tissue uptake.…”

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

“…An evaluation of the radioligand in humans has previously been reported [9]. The characteristics of this radioligand are promising, with striatal BP ND value around 7.5 in humans [9], which is higher than those reported for other PDE10A radioligands (typical range: 2–5) [8–19].…”

“…The characteristics of this radioligand are promising, with striatal BP ND value around 7.5 in humans [9], which is higher than those reported for other PDE10A radioligands (typical range: 2–5) [8–19]. Preliminary examination of [ 11 C]Lu AE92686 in cynomolgus monkeys has suggested that [ 11 C]Lu AE92686 binding is high in the striatum ( BP ND around 6.5), and the specificity of binding was demonstrated by dose-dependent reduction in uptake of [ 11 C]Lu AE92686 following the administration of PDE10A inhibitor MP-10 [9]. However, the initial study in monkeys did not include a full kinetic evaluation of [ 11 C]Lu AE92686 or examination of binding in the SN.…”

955. Striatal Phosphodiesterase 10A and Medial Prefrontal Cortical Thickness in Patients with Schizophrenia: A PET and MRI Study

“…17,46 In other striatal disorders, such as Parkinson's and Huntington's disease, similarly lower availability of striatal PDE10A has been reported before any volumetric signs of degeneration are obvious. 13,14 We explored the correlations between striatal PDE10A expression and cortical thickness to investigate the effects of a possibly altered striatal function on distant brain areas.…”

“…28 Parametric images were computed using receptor parametric mapping, a basis function implementation of the simplified reference tissue model using cerebellar gray matter as reference tissue, 29,30 and previously validated for [ 11 C]Lu AE92686. 17 To extract individual BP ND values for basal ganglia subregions and thalamus, the individual BP ND volumes were non-linearly warped to Montreal Neurological Institute standard space using a unified segmentation approach with the algorithm 'new segment' in SPM12 (http://www.fil. ion.ucl.ac.uk/spm/), running in MATLAB R2016a (http://se.mathworks.com/ products/matlab/).…”