Radiosynthesis and biological evaluation of the new PDE10A radioligand [18 F]AQ28A.

Cyclic nucleotide phosphodiesterase 10A (PDE10A) regulates the level of the second messengers cAMP and cGMP in particular in brain regions assumed to be associated with neurodegenerative and psychiatric diseases. A better understanding of the pathophysiological role of the expression of PDE10A could be obtained by quantitative imaging of the enzyme by positron emission tomography (PET). Thus, in this study we developed, radiolabeled, and evaluated a new PDE10A radioligand, 8-bromo-1-(6-[18 F]fluoropyridin-3-yl)-3,4-dimethylimidazo[1,5-a]quinoxaline ([18 F]AQ28A). [18 F]AQ28A was radiolabeled by both nucleophilic bromo-to-fluoro or nitro-to-fluoro exchange using K[18 F]F-K2.2.2 -carbonate complex with different yields. Using the superior nitro precursor, we developed an automated synthesis on a Tracerlab FX F-N module and obtained [18 F]AQ28A with high radiochemical yields (33 ± 6%) and specific activities (96-145 GBq·µmol-1 ) for further evaluation. Initially, we investigated the binding of [18 F]AQ28A to the brain of different species by autoradiography and observed the highest density of binding sites in striatum, the brain region with the highest PDE10A expression. Subsequent dynamic PET studies in mice revealed a region-specific accumulation of [18 F]AQ28A in this region, which could be blocked by preinjection of the selective PDE10A ligand MP-10. In conclusion, the data suggest [18 F]AQ28A is a suitable candidate for imaging of PDE10A in rodent brain by PET.

Novel triazines as potent and selective phosphodiesterase 10A inhibitors.

The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2 mg/kg).

Synthesis and structure-activity relationship studies of dihydronaphthyridinediones as a novel structural class of potent and selective PDE7 inhibitors.

The synthesis and SAR studies of a series of structurally novel inhibitors of PDE7 are discussed. The best compounds from the series display low nanomolar inhibitory activity and are selective versus other PDE isoenzymes.

Development of highly potent phosphodiesterase 10A (PDE10A) inhibitors: Synthesis and in vitro evaluation of 1,8-dipyridinyl- and 1-pyridinyl-substituted imidazo[1,5-a]quinoxalines.

Herein we report the synthesis of fluorinated inhibitors of phosphodiesterase 10A (PDE10A) which can be used potentially as lead structure for the development of a (18)F-labeled PDE10A imaging agent for positron emission tomography. The use of ortho-fluoropyridines as residues could potentially enable the introduction of (18)F through nucleophilic substitution for radiolabeling purposes. 2-Fluoropyridines are introduced by a Suzuki coupling at different positions of the molecule. The reference compounds, 1,8-dipyridinylimidazo[1,5-a]quinoxalines and 1-pyridinylimidazo[1,5-a]quinoxalines, show inhibitory potencies at best in the subnanomolar range and selectivity factors greater than 38 against other PDE's. 1,8-Dipyridinylimidazo[1,5-a]quinoxalines are more potent inhibitors than 1-pyridinylimidazo[1,5-a]quinoxalines. Using 2-fluoro-3-pyridinyl as residue provided the most potent inhibitors 16 (IC50 = 0.12 nM), 17 (IC50 = 0.048 nM) and 32 (IC50 = 0.037 nM).

Effect of PDE10A inhibitors on MK-801-induced immobility in the forced swim test.

RATIONALE: Negative symptoms of schizophrenia are insufficiently treated by current antipsychotics. However, research is limited by the lack of validated models. Clinical data indicate that phencyclidine (PCP) abuse may induce symptoms resembling negative symptoms in humans. Based on that, Noda et al. proposed a model of PCP-induced increase of immobility in the forced swim test in mice as a model of depression-like negative symptoms of schizophrenia. OBJECTIVES: The aim of the study was to evaluate the effect of phosphodiesterase 10A (PDE10A) inhibition in this model which was modified by using MK-801 instead of PCP. METHODS: Increase of immobility in the forced swim test was induced by repeated MK-801 treatment followed by a 2-day washout in mice. The effect of haloperidol, clozapine, risperidone and PDE10A inhibitors was evaluated in this model, on open-field activity and acute MK-801-induced hyperactivity. RESULTS: Repeated MK-801 treatment significantly increased immobility in the forced swim test without affecting open-field activity. It induced hypersensitivity to the dopamine D1 agonist A-68930, suggesting a hypofunction of the D1 pathway. The increase of immobility is reversed by clozapine and PDE10A inhibitors, but not by haloperidol. Clozapine and the PDE10A inhibitors did not enhance activity at effective doses. CONCLUSION: The possibility to substitute PCP by MK-801 in this model indicates that the effect is mediated by their common mechanism of NMDA antagonism. PDE10A inhibitors similar to clozapine significantly antagonize the increase of immobility, suggesting a therapeutic potential for the treatment of negative symptoms. However, further validation of the model is necessary.

Highly potent, selective, and orally active phosphodiesterase 10A inhibitors.

The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.