Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors (original) (raw)
Related papers
Molecules, 2015
Phosphodiesterase 2A (PDE2A) is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET). Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA2-4) and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were 18 F-radiolabelled ([ 18 F]TA3 and [ 18 F]TA4) and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain displayed region-specific distribution of [ 18 F]TA3 and [ 18 F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [ 18 F]TA3 and [ 18 F]TA4 in mice showed a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small-animal PET/MR studies in OPEN ACCESS mice using [ 18 F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [ 18 F]TA3 and [ 18 F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives.
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...
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...
Molecules (Basel, Switzerland), 2018
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...
ACS Medicinal Chemistry Letters, 2015
A novel series of pyrido[4,3-e][1,2,4]triazolo-[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12.
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...
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, 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...
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