[18F]Fluoropyridine‐losartan: A new approach toward human Positron Emission Tomography imaging of Angiotensin II Type 1 receptors

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 66; no. 3; pp. 73 - 85
• Main Authors: Abreu Diaz, Aida Mary, Rodriguez Riera, Zalua, Lee, Yanick, Esteves, Luis Miguel, Normandeau, Charles‐Olivier, Fezas, Baptiste, Hernandez Saiz, Alejandro, Tournoux, François, Juneau, Daniel, DaSilva, Jean N.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-03-2023
• Subjects: Angiotensin; Angiotensin II; Animals; Automation; Azides; Cardiovascular diseases; Chemical synthesis; Conjugation; Cu(I) stabilizing agent THPTA; CuAAC click chemistry; Decay; Dosimeters; Dosimetry; Fluorides; Fluorine isotopes; Fluorine Radioisotopes; fluorine‐18; High-performance liquid chromatography; Humans; In vivo methods and tests; Losartan; Medical imaging; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Purification; Quality control; Radiolysis; Rats; Receptors; Selective binding; Silica gel; Stabilizers (agents); Swine; fluorine-18; automation; Cu(I) stabilizing agent THPTA; CuAAC click chemistry
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.4014

Angiotensin II type 1 receptors (AT1R) blocker losartan is used in patients with renal and cardiovascular diseases. [18F]fluoropyridine‐losartan has shown favorable binding profile for quantitative renal PET imaging of AT1R with selective binding in rats and pigs, low interference of radiometabolites and appropriate dosimetry for clinical translation. A new approach was developed to produce [18F]fluoropyridine‐losartan in very high molar activity. Automated radiosynthesis was performed in a three‐step, two‐pot, and two‐HPLC‐purification procedure within 2 h. Pure [18F]FPyKYNE was obtained by radiofluorination of NO2PyKYNE and silica‐gel‐HPLC purification (40 ± 9%), preventing the formation of nitropyridine‐losartan in the second step. Conjugation with trityl‐losartan azide via click chemistry, followed by acid hydrolysis, C18‐HPLC purification and reformulation provided [18F]fluoropyridine‐losartan in 11 ± 2% (decay‐corrected from [18F]fluoride, EOB). Using tris[(1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl]‐amine (THPTA) as a Cu(I)‐stabilizing agent for coupling [18F]FPyKYNE to the unprotected losartan azide afforded [18F]fluoropyridine‐losartan in similar yields (11 ± 3%, decay‐corrected from [18F]fluoride, EOB). Reverse‐phase HPLC was optimized by reducing the pH of the mobile phase to achieve complete purification and high molar activities (467 ± 60 GBq/μmol). The use of radioprotectants prevented tracer radiolysis for 10 h (RCP > 99%). The product passed the quality control testing. This reproducible automated radiosynthesis process will allow in vivo PET imaging of AT1R expression in several diseases.
Automated radiosynthesis of [18F]fluoropyridine‐losartan was improved by silica‐gel HPLC purification of [18F]FPyKYNE, preventing the formation of nitropyridine‐losartan in the second step. Coupling with trityl‐protected or unprotected losartan azide, C18‐HPLC purification (pH 2), and reformulation (with radioprotectants) provided [18F]fluoropyridine‐losartan in high molar activities (467 ± 60 GBq/μmol) and RCP > 99% for 10 h. The product passed the quality control testing accomplished in three validation runs according to the current requirements for PET radiotracers for human use.