Evaluation of the high affinity [18F]fluoropyridine-candesartan in rats for PET imaging of renal AT1 receptors

• Published in: Nuclear medicine and biology Vol. 96-97; pp. 41 - 49
• Main Authors: Abreu Diaz, Aida M., Drumeva, Gergana O., Laporte, Philippe, Alonso Martinez, Luis M., Petrenyov, Daniil R., Carrier, Jean-François, DaSilva, Jean N.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Inc 01-05-2021; Elsevier BV
• Subjects: Affinity; Angiotensin; Angiotensin II; Angiotensin II type 1 receptor; Binding; Binding affinity; Blood; Computed tomography; Coronary artery disease; Evaluation; Fluorine isotopes; Heart diseases; High-performance liquid chromatography; IC50; Image acquisition; Inhibition constant Ki; Injection; Interference; Kidneys; Liquid chromatography; Liver; Medical imaging; Metabolites; Neuroimaging; PET imaging in rats; Plasma proteins; Positron emission; Proteins; Radiolabeled metabolites; Receptors; Renal cortex; Rodents; Selectivity; Tomography; Ultrafiltration; Angiotensin II type 1 receptor; Inhibition constant Ki; Binding affinity; PET imaging in rats; Radiolabeled metabolites; IC50
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2021.03.003

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.
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).
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.
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.
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