11C-Radiosynthesis and preliminary human evaluation of the disposition of the ACE inhibitor [11C]zofenoprilat.
(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.
Matarrese
Mario
M
Institute of Molecular Bioimaging and Physiology-CNR, University of Milano/Bicocca, Institute San Raffaele, Via Olgettina 60, 20132 Milan, Italy.
Salimbeni
Aldo
A
Turolla
Elia Anna
EA
Turozzi
Damiano
D
Moresco
Rosa Maria
RM
Poma
Davide
D
Magni
Fulvio
F
Todde
Sergio
S
Rossetti
Claudio
C
Sciarrone
Maria Teresa
MT
Bianchi
Giuseppe
G
Kienle
Marzia Galli
MG
Fazio
Ferruccio
F
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
D000806:Angiotensin-Converting Enzyme Inhibitors; D002250:Carbon Radioisotopes; C044958:zofenopril; C065520:zofenoprilate; D002216:Captopril