Radioiodination of Atorvastatin as a Model Radiopharmaceutical for Targeting Liver
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adioiodination of Atorvastatin as a Model Radiopharmaceutical for Targeting Liver Moustapha E. Moustaphaa,* a
Department of Chemistry, College of Science and Humanities, Prince Sattam bin Abdulaziz University, AlKharj, 11942 Saudi Arabia *e-mail: [email protected] Received June 30, 2019; revised August 28, 2019; accepted September 4, 2019
Abstract—Atorvastatin was radioiodinated and formulated using chloramine-T via an electrophilic substitution reaction for the development of a potential radiopharmaceutical for targeting liver. The impact of different reaction parameters and conditions that affected the labeling yield such as pH of the reaction, concentration of atorvastatin and reaction time were optimized in order to increase the radioiodination efficiency. The labeling yield was 94.3 ± 1.41 %. In vitro analysis demonstrated that the compound was steady for up to 24 h. The liver uptake was 40.35% and the clearance pathways proceed via the hepatobiliary and renal clearance. Keywords: atorvastatin, radioiodination, chloramine-T, biodistribution, liver-targeting agents DOI: 10.1134/S1066362220040104
metabolites are 2-hydroxy- and 4-hydroxy-atorvastatin acid [14, 15]. Elimination of atorvastatin occurs from the systemic circulation through the liver via the bile into the feces and through the kidneys via the renalurinary system [16–19]. Most of the hepatobiliary radiopharmaceuticals available for imaging are labeled with 99mTc. They exhibit identical pharmacokinetic properties in animals. They are efficiently removed from the blood by the liver and excreted into the bile. Moreover, they diagnose diseases of hepatocytic function and the functional status of the cystic duct and the gallbladder [6]. The mechanism of in situ oxidative radioiodination using chloramine-T (CAT), involving the formation of iodine monochloride (ICl), was elucidated [20, 21]. In weakly acidic media, CAT dissociates to ArSO2NCl– anion, which may react directly with iodide to form ICl. Subsequently the iodine monochloride (ICl) reacts with any position in the target molecule that can experience electrophilic substitution [20, 22]. Owing to the difference in the electronegativity between iodine and chlorine, ICl is highly polar and acts as a source of iodonium ion (I+). Therefore, aromatic electrophilic labeling with electropositive radioiodide usually proceeds in high radiochemical yield compared to 50% yield if molecular
INTRODUCTION Atorvastatin is a representative of lipid-lowering drug family recognized as statins. It acts selectively in the liver as inhibitor of HMG-CoA reductase and cholesterol synthesis. It is chemically described as (3R,5R)7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid [1]. The lipophilicity/hydrophilicity of the radiolabeled complexes determines the binding affinity for hepatic transport proteins, the efficiency of their hepatocyte uptake, and the excretion pathways [2, 3]. Atorvastatin is taken up selectively into the liver (hepatocytes) via organic anion-transporting
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