title: Evaluation of PET radioligands for in vivo visualization of phosphodiesterase 5 (PDE5).
abstract: BACKGROUND
  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 [(11)C]methyl trifluoromethanesulfonate ([(11)C]CH3OTf) or 2-[(18)F]fluoroethyl trifluoromethanesulfonate ([(18)F]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 [(11)C]-7 and [(18)F]-11 and the retention of the ethoxyethyl pyrazolopyrimidine derivative [(11)C]-37 was moderate. The other investigated compounds [(11)C]-8, [(11)C]-14, [(11)C]-21 and [(11)C]-33 showed lower retention in lungs in agreement with their lower in-vitro affinity for PDE5.
  
  
  CONCLUSIONS
  Among the different radiolabeled PDE5 inhibitors evaluated in this study, the vardenafil derivatives [(11)C]-7 and [(18)F]-11 are found to be promising tracers for in vivo visualization of PDE5.
authors.affiliation: KU Leuven, Laboratory of Radiopharmacy, Leuven, Belgium.
authors.forename: Rufael
authors.initials: R
authors.lastname: Chekol
authors.affiliation: KU Leuven, Department of Imaging and Pathology, Leuven, Belgium and Nuclear Medicine, UZ Leuven.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gheysens
authors.affiliation: KU Leuven, Laboratory of Radiopharmacy, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Cleynhens
authors.affiliation: KU Leuven, Departement of Cardiovascular Sciences, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Pokreisz
authors.affiliation: C.R.E.A.Te Translational Sciences, Janssen Pharmaceutica, R&D, Beerse, Belgium.
authors.forename: Greet
authors.initials: G
authors.lastname: Vanhoof
authors.affiliation: KU Leuven, Laboratory of Radiopharmacy, Leuven, Belgium.
authors.forename: Muneer
authors.initials: M
authors.lastname: Ahamed
authors.affiliation: KU Leuven, Departement of Cardiovascular Sciences, Leuven, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Janssens
authors.affiliation: KU Leuven, Laboratory of Radiopharmacy, Leuven, Belgium.
authors.forename: Alfons
authors.initials: A
authors.lastname: Verbruggen
authors.affiliation: KU Leuven, Laboratory of Radiopharmacy, Leuven, Belgium. Electronic address: guy.bormans@pharm.kuleuven.be.
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008024:Ligands; D008297:Male; D008698:Mesylates / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry
chemical_list: D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D008024:Ligands; D008698:Mesylates; D058986:Phosphodiesterase 5 Inhibitors; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C012077:trifluoromethanesulfonic acid
keywords: Cyclic guanosinemonophosphate (cGMP); Heart failure; Phosphodiesterase 5; Phosphodiesterase 5 inhibitors; Positron emission tomography (PET) tracers; Pulmonary arterial hypertension