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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.

ABSTRACT: 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 (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 [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.

SUBMITTER: Sahyli Ortega Pijeira M

PROVIDER: S-EPMC7221519 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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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.

Sahylí Ortega Pijeira Martha M Sérgio Gonçalves Nunes Paulo P Nascimento Dos Santos Sofia S Zhang Zhengxing Z Pérez Nario Arian A Araujo Perini Efrain E Miguel Turato Walter W Rodríguez Riera Zalua Z Chammas Roger R H Elsinga Philip P Lin Kuo-Shyan KS Carvalho Ivone I Soares Bernardes Emerson E

Molecules (Basel, Switzerland) 20200418 8

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 tracer ...[more]

PMID: 32325695

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Project description:PurposeThe α7 nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α7 nAChRs PET radioligands, [18F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [18F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of [18F]ASEM in humans.MethodsPET scans with high specific activity [18F]ASEM or [18F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional [18F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with [18F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of [18F]ASEM distribution volume (V T). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of V T was assessed.ResultsIn the rhesus monkey brain [18F]ASEM and [18F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of [18F]ASEM binding was observed, while administration of either nicotine or varenicline did not change [18F]ASEM V T. [18F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of [18F]ASEM V T in humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in V T values ranging from 19.6 ± 2.5 mL/cm3 in cerebellum to 25.9 ± 2.9 mL/cm3 in thalamus. Test-retest variability of V T was 11.7 ± 9.8%.ConclusionsThese results confirm [18F]ASEM as a suitable radiotracer for the imaging and quantification of α7 nAChRs in humans.

Project description:Podocytes are highly specialized cells that play a pivotal role in the blood filtration process in the glomeruli of the kidney, and their dysfunction leads to renal diseases. For this reason, the study and application of this cell type is of great importance in the field of regenerative medicine. Hypertension is mainly regulated by the renin-angiotensin-aldosterone system (RAAS), with its main mediator being angiotensin II (ANG II). Elevated ANG II levels lead to a pro-fibrotic, inflammatory, and hypertrophic milieu that induces apoptosis in podocytes. The activation of RAAS is critical for the pathogenesis of podocyte injury; as such, to prevent podocyte damage, patients with hypertension are administered drugs that modulate RAAS signaling. A prime example is the orally active, non-peptide, selective angiotensin-II-type I receptor (AGTR1) blocker losartan. Here, we demonstrate that SIX2-positive urine-derived renal progenitor cells (UdRPCs) and their immortalized counterpart (UM51-hTERT) can be directly differentiated into mature podocytes. These podocytes show activation of RAAS after stimulation with ANG II, resulting in ANG II-dependent upregulation of the expression of the angiotensin-II-type I receptor, AGTR1, and the downregulated expression of the angiotensin-II-type II receptor 2 (AGTR2). The stimulation of podocytes with losartan counteracts ANG II-dependent changes, resulting in a dependent favoring of the specific receptor from AGTR1 to AGTR2. Transcriptome analysis revealed 94 losartan-induced genes associated with diverse biological processes and pathways such as vascular smooth muscle contraction, the oxytocin signaling pathway, renin secretion, and ECM-receptor interaction. Co-stimulation with losartan and ANG II induced the exclusive expression of 106 genes associated with DNA methylation or demethylation, cell differentiation, the developmental process, response to muscle stretch, and calcium ion transmembrane transport. These findings highlight the usefulness of UdRPC-derived podocytes in studying the RAAS pathway and nephrotoxicity in various kidney diseases.

Dataset Information

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

Publications

Synthesis and Evaluation of [<sup>18</sup>F]FEtLos and [<sup>18</sup>F]AMBF<sub>3</sub>Los as Novel <sup>18</sup>F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors.

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