Publications by authors named "N Hoefgen"

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-[ F]fluoropyridin-3-yl)-3,4-dimethylimidazo[1,5-a]quinoxaline ([ F]AQ28A).

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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.

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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.

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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.

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Article Synopsis
  • Researchers developed new phenylpyrazine compounds that effectively inhibit the PDE10A enzyme, achieving subnanomolar potency and high selectivity against other PDE family members.
  • They used structure-based drug design to modify the parent compound to enhance its binding affinity and reduce mutagenicity by adding bulky substituents.
  • One potent compound, referred to as 96, showed an impressive IC(50) of 0.7 nM for PDE10A and proved effective in animal models relevant for antipsychotic treatments.
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