title: 11C-Radiosynthesis and preliminary human evaluation of the disposition of the ACE inhibitor [11C]zofenoprilat.
abstract: (4S)-1-[(S)-3-Mercapto-2-methylpropanoyl]-4-phenylthio-L-proline (Zofenoprilat, 2), the active metabolite of the potent ACE inhibitor Zofenopril Calcium (1), was labelled with carbon-11 (t1/2=20.4 min) to evaluate its pharmacokinetics behaviour in human body using Positron Emission Tomography (PET). [11C]2 labelling procedures were based on the use of immobilized Grignard reagent and the acylation of (S)-4-phenylthio-L-proline methyl ester (5) with 11C-labelled methacryloyl chloride, followed by a Michael addition with thiobenzoic acid. The radiochemical yield was 5-10% (EOB, decay corrected) and specific radioactivity ranged from 0.5 to 1.5 Ci/micromol (18.5-55.5 GBq/micromol). Preliminary in vivo human evaluation of [11C]2 showed that the drug accumulates in organs which express high levels of ACE, like lungs and kidneys, and in organs involved in drug metabolism such as the liver and gall bladder. Results of the distribution of [11C]2 showed a measurable concentration of the drug in the target tissues such as the kidney and to a minor extent, the heart, where it can afford organ protection.
authors.affiliation: Institute of Molecular Bioimaging and Physiology-CNR, University of Milano/Bicocca, Institute San Raffaele, Via Olgettina 60, 20132 Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Matarrese
authors.forename: Aldo
authors.initials: A
authors.lastname: Salimbeni
authors.forename: Elia Anna
authors.initials: EA
authors.lastname: Turolla
authors.forename: Damiano
authors.initials: D
authors.lastname: Turozzi
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Moresco
authors.forename: Davide
authors.initials: D
authors.lastname: Poma
authors.forename: Fulvio
authors.initials: F
authors.lastname: Magni
authors.forename: Sergio
authors.initials: S
authors.lastname: Todde
authors.forename: Claudio
authors.initials: C
authors.lastname: Rossetti
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Sciarrone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bianchi
authors.forename: Marzia Galli
authors.initials: MG
authors.lastname: Kienle
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Fazio
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D002216:Captopril / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D006801:Humans; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002250:Carbon Radioisotopes; C044958:zofenopril; C065520:zofenoprilate; D002216:Captopril