Synthesis and Evaluation of [F-18]FEtLos and [F-18]AMBF(3)Los as Novel F-18-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors

Author(s):Show less -

Ortega Pijeira, Martha Sahyli ^[1] ; Goncalves Nunes, Paulo Sergio ^[2] ; dos Santos, Sofia Nascimento ^[1] ; Zhang, Zhengxing ^[3] ; Nario, Arian Perez ^[1] ; Perini, Efrain Araujo ^[1] ; Turato, Walter Miguel ^[4] ; Riera, Zalua Rodriguez ^[5] ; Chammas, Roger ^[6] ; Elsinga, Philip H. ^[7] ; Lin, Kuo-Shyan ^[3] ; Carvalho, Ivone ^[2] ; Bernardes, Emerson Soares ^[1]

Affiliation

^[1] Nucl & Energy Res Inst IPEN CNEN SP, Radiopharm Ctr, BR-05508000 Sao Paulo - Brazil

^[2] Univ Sao Paulo FCFRP USP, Sch Pharmaceut Sci Ribeirao Preto, BR-14040903 Ribeirao Preto - Brazil

^[3] BC Canc Res Ctr, Dept Mol Oncol, Vancouver, BC V5Z 1L3 - Canada

^[4] Univ Sao Paulo, Sch Pharmaceut Sci, BR-05508000 Sao Paulo - Brazil

^[5] Univ La Habana, Dept Radioquim, Inst Super Tecnol & Ciencias Aplicadas InSTEC, Havana 10400 - Cuba

^[6] Univ Sao Paulo, Fac Med, Dept Radiol & Oncol, BR-01246903 Sao Paulo - Brazil

^[7] Univ Groningen, Univ Med Ctr Groningen, Dept Nucl Med & Mol Imaging, EB79, POB 30-001, NL-9700 RB Groningen - Netherlands

• Document type: Journal article
• Source: Molecules; v. 25, n. 8 APR 2 2020.
• Web of Science Citations: 0

Abstract

Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT(1)Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT(1)R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, {[}F-18]fluoroethyl-losartan ({[}F-18]FEtLos) and {[}F-18]ammoniomethyltrifluoroborate-losartan ({[}F-18]AMBF(3)Los). {[}F-18]FEtLos was radiolabeled by F-18-fluoroalkylation of losartan potassium using the prosthetic group 2-{[}F-18]fluoroethyl tosylate; whereas {[}F-18]AMBF(3)Los was prepared following an one-step F-18-F-19 isotopic exchange reaction, in an overall yield of 2.7 +/- 0.9% and 11 +/- 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT(1)R-expressing membranes showed that AMBF(3)Los presented an almost equivalent binding affinity (K-i 7.9 nM) as the cold reference Losartan (K-i 1.5 nM), unlike FEtLos (K-i 2000 nM). In vitro and in vivo assays showed that {[}F-18]AMBF(3)Los displayed a good binding affinity for AT(1)R-overexpressing CHO cells and was able to specifically bind to renal AT(1)R. Hence, our data demonstrate {[}F-18]AMBF(3)Los as a new tool for PET imaging of AT(1)R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases. (AU)

• FAPESP's process: 12/06875-6 - Development and production of positron emission tomography radiopharmaceuticals for diagnostic purposes in oncology
• Grantee: Emerson Soares Bernardes
• Support Opportunities: Research Grants - Young Investigators Grants