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

被引：7

作者：

Chekol, Rufael ^{[1
,6
]}

Gheysens, Olivier ^{[2
,3
]}

Ahamed, Muneer ^{[1
]}

Cleynhens, Jan ^{[1
]}

Pokreisz, Peter ^{[4
]}

Vanhoof, Greet ^{[5
]}

Janssens, Stefan ^{[4
]}

Verbruggen, Alfons ^{[1
]}

Bormans, Guy ^{[1
]}

机构：

[1] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Lab Radiopharm, BE-3000 Leuven, Belgium

[2] Katholieke Univ Leuven, Dept Imaging & Pathol, BE-300 Leuven, Belgium

[3] UZ Leuven, Nucl Med, BE-300 Leuven, Belgium

[4] Katholieke Univ Leuven, UZ Leuven, Dept Cardiovasc Sci, B-3000 Leuven, Belgium

[5] Janssen Pharmaceut R&D, Discovery Sci, B-2340 Beerse, Belgium

[6] Univ Sasketchewan, Coll Med, Med Imaging, Saskatoon, SK, Canada

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 01期

关键词：

SYSTOLIC HEART-FAILURE; PULMONARY-HYPERTENSION; INHIBITION; EXPRESSION; SILDENAFIL; TYPE-5; BRAIN; POTENT;

D O I：

10.1021/acs.jmedchem.6b01666

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDES) plays an important role in various pathologies including pulmonary arterial hypertension and cardiomyopathy. PDES 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 [C-11]-12 and [F-18]-17 in the lungs of wild-type mice and in the myocardium of transgenic mice with cardiomyocyte-specific PDES 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 [C-11]-.1.2 and [F-18]-17 showed specific binding to PDE5 in myocardium of transgenic mice; however [F-18]-11 showed significantly higher PDE5-specific inhibitable binding than [C-11]-12.

引用

页码：486 / 496

页数：11

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