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

  • J Labelled Comp Radiopharm. 2023 Mar;66(3):73-85. doi: 10.1002/jlcr.4014.
Aida Mary Abreu Diaz  1  2  3  4 ,  Zalua Rodriguez Riera  4 ,  Yanick Lee  1  3 ,  Luis Miguel Esteves  1  5 ,  Charles-Olivier Normandeau  1 ,  Baptiste Fezas  1 ,  Alejandro Hernandez Saiz  1 ,  François Tournoux  1  6 ,  Daniel Juneau  1  7  8 ,  Jean N DaSilva  1  2  3  8
Affiliations
  • 1. Laboratoire de Radiochimie et Cyclotron, Centre de Recherche du CHUM, Montréal, Québec, Canada.
  • 2. Département de pharmacologie et physiologie, Faculté de médecine, Université de Montréal, Pavillon Paul-G. Desmarais, Montréal, Québec, Canada.
  • 3. Institut de génie biomédical, Faculté de médecine, Université de Montréal, Pavillon Paul-G. Desmarais, Montréal, Québec, Canada.
  • 4. Departamento de Radioquímica, Instituto Superior de Tecnologías y Ciencias Aplicadas, Universidad de la Habana, La Habana, Cuba.
  • 5. CRCHUM site, Isologic Innovative Radiopharmaceuticals, Lachine, Québec, Canada.
  • 6. Centre cardiovasculaire, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
  • 7. Médecine nucléaire, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
  • 8. Département de radiologie, radio-oncologie et médecine nucléaire, Faculté de médecine, Université de Montréal, Pavillon Roger-Gaudry, Montréal, Québec, Canada.
PMID: 36656923 DOI: 10.1002/jlcr.4014
Abstract

Angiotensin II type 1 receptors (AT1 R) blocker losartan is used in patients with renal and cardiovascular diseases. [18 F]fluoropyridine-losartan has shown favorable binding profile for quantitative renal PET imaging of AT1 R with selective binding in rats and pigs, low interference of radiometabolites and appropriate dosimetry for clinical translation. A new approach was developed to produce [18 F]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 [18 F]FPyKYNE was obtained by radiofluorination of NO2 PyKYNE 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 [18 F]fluoropyridine-losartan in 11 ± 2% (decay-corrected from [18 F]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 [18 F]FPyKYNE to the unprotected losartan azide afforded [18 F]fluoropyridine-losartan in similar yields (11 ± 3%, decay-corrected from [18 F]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 AT1 R expression in several diseases.

Keywords
Cu(I) stabilizing agent THPTA; CuAAC click chemistry; automation; fluorine-18.
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