title: Synthesis, radiolabeling and in vivo evaluation of [11C]RAL-01, a potential phosphodiesterase 5 radioligand.
abstract: Very few tracers are available for imaging studies of second messenger systems. We developed a radiosynthesis for the phosphodiesterase (PDE) 5 inhibitor [(11)C]RAL-01. Whole body distribution studies using positron emission tomography (PET) revealed a time-dependant passage through the liver and accumulation of radioactivity in the bile of the Landrace pig. Displaceable binding was readily discerned in the myocardium, and traces of binding were seen in pulmonary tissue, consistent with the use of this class of drug in the treatment of pulmonary hypertension and heart failure. [(11)C]RAL-01 readily entered the brain and obtained an equilibrium distribution volume of 4-5 ml g(-1). Mean parametric images suggested the presence of a small displaceable binding component, but this binding was not significant in the present group of three pigs. Thus, [(11)C]RAL-01 shows considerable promise for PET studies of biliary elimination and of PDE5 binding in the cardiovascular system. However, analogues of higher affinity may be required for investigations of central nervous system binding sites.
authors.affiliation: PET Centre, Aarhus University Hospitals, 8000 Aarhus, Denmark. steen@pet.auh.dk
authors.forename: Steen
authors.initials: S
authors.lastname: Jakobsen
authors.forename: Gitte Munkebo
authors.initials: GM
authors.lastname: Kodahl
authors.forename: Aage Kristian
authors.initials: AK
authors.lastname: Olsen
authors.forename: Paul
authors.initials: P
authors.lastname: Cumming
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002243:Carbolines / Q000737:chemistry / Q000493:pharmacokinetics*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004353:Drug Evaluation, Preclinical; D005240:Feasibility Studies; D007553:Isotope Labeling / Q000379:methods; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay / Q000379:methods; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013552:Swine; D014018:Tissue Distribution; D051598:Whole Body Imaging
chemical_list: C513929:2-butyl-5-(4-hydroxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo(1',5'-1,6)pyrido(3,4-b)indole-1,3(2H)-dione; D002243:Carbolines; D019275:Radiopharmaceuticals; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5