Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain (original) (raw)
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Journal of medicinal chemistry, 2016
The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) plays an important role in various pathologies including pulmonary arterial hypertension and cardiomyopathy. PDE5 represents an important therapeutic and/or prognostic target, but noninvasive assessment of PDE5 expression is lacking. The purpose of this study was to develop and evaluate pyridopyrazinone derivatives labeled with carbon-11 or fluorine-18 as PDE5-specific PET tracers. In biodistribution studies, highest PDE5-specific retention was observed for [(11)C]-12 and [(18)F]-17 in the lungs of wild-type mice and in the myocardium of transgenic mice with cardiomyocyte-specific PDE5 overexpression at 30 min postinjection. In vivo dynamic microPET images in rats revealed that both tracers crossed the blood-brain barrier but brain retention was not PDE5-specific. Both [(11)C]-12 and [(18)F]-17 showed specific binding to PDE5 in myocardium of transgenic mice; however [(18)F]-17 showed significantly hi...
Molecules
A specific radioligand for the imaging of cyclic nucleotide phosphodiesterase 2A (PDE2A) via positron emission tomography (PET) would be helpful for research on the physiology and disease-related changes in the expression of this enzyme in the brain. In this report, the radiosynthesis of a novel PDE2A radioligand and the subsequent biological evaluation were described. Our prospective compound 1-(2-chloro-5-methoxy phenyl)-8-(2-fluoropyridin-4-yl)-3- methylbenzo[e]imidazo[5,1-c][1,2,4]triazine, benzoimidazotriazine (BIT1) (IC50 PDE2A = 3.33 nM; 16-fold selectivity over PDE10A) was fluorine-18 labeled via aromatic nucleophilic substitution of the corresponding nitro precursor using the K[18F]F‐K2.2.2‐carbonate complex system. The new radioligand [18F]BIT1 was obtained with a high radiochemical yield (54 ± 2%, n = 3), a high radiochemical purity (≥99%), and high molar activities (155–175 GBq/μmol, n = 3). In vitro autoradiography on pig brain cryosections exhibited a heterogeneous spa...
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Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, theF-labelling as well as the biological evaluation of our latest PDE2A (radio-)ligand 9-(5-Butoxy-2-fluorophenyl)-2-(2-([F])fluoroethoxy)-7-methylimidazo[5,1-]pyrido[2,3-][1,2,4]triazine (([F])). It is the most potent PDE2A ligand out of our series of imidazopyridotriazine-based derivatives so far (IChPDE2A = 3.0 nM; IChPDE10A > 1000 nM). Radiolabelling was performed in a one-step procedure starting from the corresponding tosylate precursor. In vitro autoradiography on rat and pig brain slices displayed a homogenous and non-specific binding of the radioligand. Investigation of stability in vivo by reversed-phase HPLC (RP-HPLC) and micellar liquid chromatography (MLC) analyses of plasma and brain samples obtained from mice revealed a high fra...
Journal of medicinal chemistry, 2015
A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [(11)C]MP-10. 20 of the 22 new analogues had high potency and selectivity for PDE10A: 18a-j, 19d-j, 20a-b, and 21b had IC50 values <5 nM for PDE10A. Seven F-18 labeled compounds [(18)F]18a-e, [(18)F]18g, and [(18)F]20a were radiosynthesized by (18)F-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed ~2-fold higher activity in the PDE10A-enriched striatum than non-target brain regions; this ratio increased from 5 to 30 min post-injection, particularly for [(18)F]18a-d and [(18)F]20a. MicroPET studies of [(18)F]18d and [(18)F]20a in nonhuman primates provided clear visualization of striatum with suitable equilibrium kinetics and favorable metabolic stability. These results suggest this strategy may identify a (18)F-labeled PET tracer for quantifying the l...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2016
The enzyme phosphodiesterase 2A (PDE2A) is a potential target for development of novel therapeutic agents for the treatment of cognitive impairments. The goal of the present study was to evaluate the PDE2A ligand (18)F-PF-0150270430, 4-(3-fluoroazetidin-1-yl)-7-methyl-5-(1-methyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)imidazo[1,5-f][1,2,4]triazine, in nonhuman primates. (18)F-PF-05270430 was radiolabeled by two methods via nucleophilic substitution of its tosylate precursor. Tissue metabolite analysis in rodents and positron emission tomography (PET) imaging in non-human primates under baseline and blocking conditions were performed to determine the pharmacokinetic and binding characteristics of the new radioligand. Various kinetic modeling approaches were assessed to select the optimal method for analysis of imaging data. (18)F-PF-05270430 was synthesized in >98% radiochemical purity and high specific activity. In the non-human primate brain, uptake of (18)F-PF-05270430 w...
spectra for compound 8 and the nitro precursor 28 and peak assignments 2. Selectivity profile of compound 1 in CEREP ® panel and the PDE selectivity panel 3. Selectivity profile of compound 8 in CEREP ® panel and the PDE selectivity panel 4. NeuroPK study of compound 8 in male Wistar-Han rats 5. Protocols for the preparation of recombinant full length human PDE4A3, 4B1, 4C1 and 4D3. 6. In vitro autoradiography of [ 3 H]-1 in mice brain 7. The PDE selectivity profile of the PDE4B-preferring inhibitor used as the blocking compound in in vitro autoradiography and NHP PET imaging experiments 1. 1 H NMR and 13 C NMR spectra for compound 8 (PF-06445974) and the nitro precursor 28 and peak assignments
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2014
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. 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. (11)C-Lu AE92686 displayed high specificity a...
The Journal of Nuclear Medicine, 2014
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)-4phenyl-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-4yl-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.
Development of Radiolabeled PET Tracers for In Vivo Visualization of Phosphodiesterase Type 5 (PDE5)
2014
The research work would not have been possible without the collaboration between different departments: Department of Imaging and Pathology (KU Leuven) and Nuclear Medicine (UZ Leuven) for production of radiolabeled compounds (from radionuclide production to formulation and quality control), Nuclear Medicine and Molecular Imaging (MoSAIC, KU Leuven) for animal experiments, Department of Cardiovascular Sciences (KU Leuven) for providing transgenic mice, pig for PET study, TAC and LAD mice and their expert advice on cardiac hypertrophy, Discovery Sciences (Janssen Pharmaceutica) for determination of in vitro phosphodiesterase inhibitory activity of compounds discussed in this dissertation. I have to extend my acknowledgement and appreciation for aforementioned departments and organizations for their contribution to the success of this research work and the resulting manuscript. We (Nuclear Medicine, UZ Leuven and Radiopharmacy, KU Leuven) are truly two big and happy families. The collaboration is an amazing experience and an example to others. I would like to take this opportunity to express my gratitude to the members of this big family: Prof. Koen Van Laere (Head of Nuclear Medicine, UZ Leuven), Tjibbe De Groot and Marva Bex you were always willing to help me during radioisotope production despite the hectic situation during working hours. Tjibbe you were always forthright spoken and I like that character of yours! Bert Vanbilloen (thanks for the supervision during my first year in post graduate studies), Stef Verschoren (for the nice after-work hours :), Christelle Terwinghe; Nathalie Devolder; Mireille Heroes; Anja Wilberts; Mieke Steukers; Magdalena Sojka; Kim Serdons, Kim Deliege; Katrien Seré and Annemie Morel: thank you all for the help and nice time. Jan Cleynhens, thank you for your great work and help on the organic synthesis of molecules. Your presence in the lab made a big difference both scientifically and socially and you were the spice of the lab! Sofie thank you for valuable and practical input. Ivan, Julie and Jana: thank you for your technical assistance during animal experiments. Maarten, thank you for your help on microPET image processing and also for the great time we had while on lab trip (Parma, Amsterdam...). Ahamed, thank you for your help on organic synthesis and NMR elucidation. I greatly appreciate for forwarding links to job postings and also for little chitchats we had.