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

Rufael Chekol; Olivier Gheysens; Muneer Ahamed; Jan Cleynhens; Peter Pokreisz; Greet Vanhoof; Stefan Janssens; Alfons Verbruggen; Guy Bormans

doi:10.1021/acs.jmedchem.6b01666

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

Rufael Chekol, Olivier Gheysens, Muneer Ahamed, Jan Cleynhens, Peter Pokreisz, Greet Vanhoof, Stefan Janssens, Alfons Verbruggen, Guy Bormans

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

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

Original language	English
Pages (from-to)	486-496
Number of pages	11
Journal	Journal of medicinal chemistry
Volume	60
Issue number	1
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01666
Publication status	Published or Issued - 12 Jan 2017
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Chekol, R., Gheysens, O., Ahamed, M., Cleynhens, J., Pokreisz, P., Vanhoof, G., Janssens, S., Verbruggen, A., & Bormans, G. (2017). Carbon-11 and Fluorine-18 Radiolabeled Pyridopyrazinone Derivatives for Positron Emission Tomography (PET) Imaging of Phosphodiesterase-5 (PDE5). Journal of medicinal chemistry, 60(1), 486-496. https://doi.org/10.1021/acs.jmedchem.6b01666

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

abstract = "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]-12 and [18F]-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 [11C]-12 and [18F]-17 showed specific binding to PDE5 in myocardium of transgenic mice; however [18F]-17 showed significantly higher PDE5-specific inhibitable binding than [11C]-12.",

author = "Rufael Chekol and Olivier Gheysens and Muneer Ahamed and Jan Cleynhens and Peter Pokreisz and Greet Vanhoof and Stefan Janssens and Alfons Verbruggen and Guy Bormans",

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Chekol, R, Gheysens, O, Ahamed, M, Cleynhens, J, Pokreisz, P, Vanhoof, G, Janssens, S, Verbruggen, A & Bormans, G 2017, 'Carbon-11 and Fluorine-18 Radiolabeled Pyridopyrazinone Derivatives for Positron Emission Tomography (PET) Imaging of Phosphodiesterase-5 (PDE5)', Journal of medicinal chemistry, vol. 60, no. 1, pp. 486-496. https://doi.org/10.1021/acs.jmedchem.6b01666

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AU - Chekol, Rufael

AU - Gheysens, Olivier

AU - Ahamed, Muneer

AU - Cleynhens, Jan

AU - Pokreisz, Peter

AU - Vanhoof, Greet

AU - Janssens, Stefan

AU - Verbruggen, Alfons

AU - Bormans, Guy

PY - 2017/1/12

Y1 - 2017/1/12

N2 - 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]-12 and [18F]-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 [11C]-12 and [18F]-17 showed specific binding to PDE5 in myocardium of transgenic mice; however [18F]-17 showed significantly higher PDE5-specific inhibitable binding than [11C]-12.

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

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

Abstract

ASJC Scopus subject areas

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