Evaluation of the high affinity [18F]fluoropyridine-candesartan in rats for PET imaging of renal AT1 receptors
Autor: | Gergana O. Drumeva, Philippe Laporte, Luis Michel Alonso Martinez, Jean-François Carrier, Aida M. Abreu Diaz, Daniil R. Petrenyov, Jean N. DaSilva |
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Rok vydání: | 2021 |
Předmět: |
Cancer Research
Angiotensin II receptor type 1 Chemistry Antagonist Pharmacology Angiotensin II Blood proteins 030218 nuclear medicine & medical imaging 03 medical and health sciences Candesartan 0302 clinical medicine Losartan In vivo 030220 oncology & carcinogenesis medicine Molecular Medicine Radiology Nuclear Medicine and imaging Receptor medicine.drug |
Zdroj: | Nuclear Medicine and Biology. :41-49 |
ISSN: | 0969-8051 |
Popis: | Introduction Alterations in the expression of the Angiotensin II type 1 receptors (AT1R) have been demonstrated in the development of several heart and renal diseases. The aim of this study was to evaluate the novel compound [18F]fluoropyridine-candesartan as a PET imaging tracer of AT1R in rat kidneys. Methods Competition binding assays were carried out with membranes from CHO-K1 cells expressing human AT1R. Binding to plasma proteins was assessed by ultrafiltration. Radiolabeled metabolites in rat plasma and kidneys of control and pretreated animals (candesartan 10 mg/kg or losartan 30 mg/kg) were analyzed by column-switch HPLC. Dynamic PET/CT images of [18F]fluoropyridine-candesartan in male Sprague-Dawley rats were acquired for 60 min at baseline, pre-treatment with the AT1R antagonist losartan (30 mg/kg) or the AT2R antagonist PD123,319 (5 mg/kg). Results Fluoropyridine-candesartan bound with a high affinity for AT1R (Ki = 5.9 ± 1.1 nM), comparable to fluoropyridine-losartan but lower than the parent compound candesartan (Ki = 0.4 ± 0.1 nM). [18F]Fluoropyridine-candesartan bound strongly to plasma proteins (99.3%) and was mainly metabolized to radiolabeled hydrophilic compounds, displaying minimal interference on renal AT1R binding with 82% of unchanged tracer in the kidneys at 20 min post-injection. PET imaging displayed high renal and liver accumulations and slow clearances, with maximum tissue-to-blood ratios of 14 ± 3 and 54 ± 12 in kidney cortex and liver, respectively, at 10 min post-injection. Binding specificity for AT1R was demonstrated with marked reductions in kidney cortex (−84%) and liver (−93%) tissue-to-blood ratios at 20 min post-injection, when blocking with AT1R antagonist losartan (30 mg/kg). No change was observed in kidney cortex of rats pre-treated with AT2R antagonist PD 123,319 (5 mg/kg), confirming binding selectivity for AT1 over AT2 receptors. Conclusion High kidney-to-blood ratios and binding selectivity to renal AT1R combined with tracer in vivo stability displaying minimal interference from labeled metabolites support further PET imaging studies with [18F]fluoropyridine-candesartan. |
Databáze: | OpenAIRE |
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