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Synthesis and Evaluation of [18F]FEtLos and [18F]AMBF3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors

1
Radiopharmacy Center, Nuclear and Energy Research Institute (IPEN/CNEN-SP), CEP 05508-000 São Paulo, Brazil
2
School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (FCFRP–USP), CEP 14040-903 Ribeirão Preto, Brazil
3
Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada
4
School of Pharmaceutical Sciences–University of São Paulo-USP, CEP 05508-000 São Paulo, Brazil
5
Departamento de Radioquímica, Instituto Superior de Tecnologías y Ciencias Aplicadas (InSTEC), Universidad de La Habana, CP 10400 La Habana, Cuba
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Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, CEP 01246903 São Paulo, Brazil
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Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Internal Post code: EB79, PO box 30.001, 9700 RB Groningen, The Netherlands
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(8), 1872; https://doi.org/10.3390/molecules25081872
Received: 16 December 2019 / Revised: 18 January 2020 / Accepted: 23 January 2020 / Published: 18 April 2020
Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT1Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT1R 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, [18F]fluoroethyl-losartan ([18F]FEtLos) and [18F]ammoniomethyltrifluoroborate-losartan ([18F]AMBF3Los). [18F]FEtLos was radiolabeled by 18F-fluoroalkylation of losartan potassium using the prosthetic group 2-[18F]fluoroethyl tosylate; whereas [18F]AMBF3Los was prepared following an one-step 18F-19F 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 AT1R-expressing membranes showed that AMBF3Los presented an almost equivalent binding affinity (Ki 7.9 nM) as the cold reference Losartan (Ki 1.5 nM), unlike FEtLos (Ki 2000 nM). In vitro and in vivo assays showed that [18F]AMBF3Los displayed a good binding affinity for AT1R-overexpressing CHO cells and was able to specifically bind to renal AT1R. Hence, our data demonstrate [18F]AMBF3Los as a new tool for PET imaging of AT1R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases. View Full-Text
Keywords: fluoroethyl-losartan; [18F]FEtLos; ammoniomethyltrifluoroborate-losartan; [18F]AMBF3Los; angiotensin II type 1 receptors; [18F]Fluoroethylation; 18F-19F isotopic exchange approach; in vitro assays; µPET imaging; renal autoradiography fluoroethyl-losartan; [18F]FEtLos; ammoniomethyltrifluoroborate-losartan; [18F]AMBF3Los; angiotensin II type 1 receptors; [18F]Fluoroethylation; 18F-19F isotopic exchange approach; in vitro assays; µPET imaging; renal autoradiography
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MDPI and ACS Style

Sahylí Ortega Pijeira, M.; Sérgio Gonçalves Nunes, P.; Nascimento dos Santos, S.; Zhang, Z.; Pérez Nario, A.; Araujo Perini, E.; Miguel Turato, W.; Rodríguez Riera, Z.; Chammas, R.; H. Elsinga, P.; Lin, K.-S.; Carvalho, I.; Soares Bernardes, E. Synthesis and Evaluation of [18F]FEtLos and [18F]AMBF3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors. Molecules 2020, 25, 1872.

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