Carbon-11 and Fluorine-18 Radiolabeled Pyridopyrazinone Derivatives for Positron Emission Tomography (PET) Imaging of Phosphodiesterase‑5 (PDE5)

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 [¹¹C]-<b>12</b> and [¹⁸F]-<b>17</b> 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 [¹¹C]-<b>12</b> and [¹⁸F]-<b>17</b> showed specific binding to PDE5 in myocardium of transgenic mice; however [¹⁸F]-<b>17</b> showed significantly higher PDE5-specific inhibitable binding than [¹¹C]-<b>12</b>

Pyrido[4,3‑<i>e</i>][1,2,4]triazolo[4,3‑<i>a</i>]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

A novel series of pyrido­[4,3-<i>e</i>]­[1,2,4]­triazolo­[4,3-<i>a</i>]­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 <i>in vivo</i> receptor occupancy data are given for two representative compounds <b>6</b> and <b>12</b>

Additional file 2: of Striatal phosphodiesterase 10A availability is altered secondary to chronic changes in dopamine neurotransmission

PDE10A binding potential and supplier of rats. Overview of baseline BPND values acquired in Wistar rats supplied by Harlan and Janvier. Baseline BPND values acquired in rats from Janvier were significantly higher compared to baseline BPND values acquired in rats from Harlan (Non parametric Mann-Whitney test, p = 0.0012). (DOCX 33 kb

Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia.

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo­[1,2-<i>a</i>]­pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound <b>25a</b> for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure–activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead <b>25a</b> are described