TY - JOUR
T1 - Evaluation of PET radioligands for in vivo visualization of phosphodiesterase 5 (PDE5)
AU - Chekol, Rufael
AU - Gheysens, Olivier
AU - Cleynhens, Jan
AU - Pokreisz, Peter
AU - Vanhoof, Greet
AU - Ahamed, Muneer
AU - Janssens, Stefan
AU - Verbruggen, Alfons
AU - Bormans, Guy
PY - 2014/2
Y1 - 2014/2
N2 - Introduction: The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) is considered to play an important role in various etiologies such as pulmonary arterial hypertension (PAH) and chronic heart failure. This PDE5 modulation represents an important prognostic and/or therapeutic target; however, there is currently no method to non-invasively evaluate the PDE5 expression levels in vivo. Methods: Radiolabeled tracers were prepared by N-alkylation of the corresponding precursors with [11C]methyl trifluoromethanesulfonate ([11C]CH3OTf) or 2-[18F]fluoroethyl trifluoromethanesulfonate ([18F]FEtOTf). Biodistribution of radiolabeled tracers was studied in NMRI mice and their specific binding to PDE5 was investigated by comparing their lung retention as the enzyme is abundantly expressed in this organ. Results: The overall radiochemical yields ranged between 24% and 60% for labeled radiotracers with radiochemical purity of>99%. The highest retention in the lungs at 30min post injection was observed for vardenafil derivatives [11C]-7 and [18F]-11 and the retention of the ethoxyethyl pyrazolopyrimidine derivative [11C]-37 was moderate. The other investigated compounds [11C]-8, [11C]-14, [11C]-21 and [11C]-33 showed lower retention in lungs in agreement with their lower in-vitro affinity for PDE5. Conclusion: Among the different radiolabeled PDE5 inhibitors evaluated in this study, the vardenafil derivatives [11C]-7 and [18F]-11 are found to be promising tracers for in vivo visualization of PDE5.
AB - Introduction: The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) is considered to play an important role in various etiologies such as pulmonary arterial hypertension (PAH) and chronic heart failure. This PDE5 modulation represents an important prognostic and/or therapeutic target; however, there is currently no method to non-invasively evaluate the PDE5 expression levels in vivo. Methods: Radiolabeled tracers were prepared by N-alkylation of the corresponding precursors with [11C]methyl trifluoromethanesulfonate ([11C]CH3OTf) or 2-[18F]fluoroethyl trifluoromethanesulfonate ([18F]FEtOTf). Biodistribution of radiolabeled tracers was studied in NMRI mice and their specific binding to PDE5 was investigated by comparing their lung retention as the enzyme is abundantly expressed in this organ. Results: The overall radiochemical yields ranged between 24% and 60% for labeled radiotracers with radiochemical purity of>99%. The highest retention in the lungs at 30min post injection was observed for vardenafil derivatives [11C]-7 and [18F]-11 and the retention of the ethoxyethyl pyrazolopyrimidine derivative [11C]-37 was moderate. The other investigated compounds [11C]-8, [11C]-14, [11C]-21 and [11C]-33 showed lower retention in lungs in agreement with their lower in-vitro affinity for PDE5. Conclusion: Among the different radiolabeled PDE5 inhibitors evaluated in this study, the vardenafil derivatives [11C]-7 and [18F]-11 are found to be promising tracers for in vivo visualization of PDE5.
KW - Cyclic guanosinemonophosphate (cGMP)
KW - Heart failure
KW - Phosphodiesterase 5
KW - Phosphodiesterase 5 inhibitors
KW - Positron emission tomography (PET) tracers
KW - Pulmonary arterial hypertension
UR - https://doi.org/10.1016/j.nucmedbio.2013.10.007
UR - http://www.scopus.com/inward/record.url?scp=84892952979&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2013.10.007
DO - 10.1016/j.nucmedbio.2013.10.007
M3 - Article
SN - 0969-8051
VL - 41
SP - 155
EP - 162
JO - NUCLEAR MEDICINE AND BIOLOGY
JF - NUCLEAR MEDICINE AND BIOLOGY
IS - 2
ER -
