Abstract | PURPOSE: METHODS: Eight novel allysine-targeting chelators, PIF-1, PIF-2, …, PIF-8, with different aldehyde-reactive moieties were designed, synthesized, and radiolabeled with gallium-68 or copper-64. PET probe performance was assessed in C57BL/6J male mice 2 weeks after intratracheal bleomycin challenge and in naïve mice by dynamic PET/MR imaging and with biodistribution at 90 min post injection. Lung hydroxyproline and allysine were quantified ex vivo and histological staining for fibrosis and aldehyde was performed. RESULTS: In vivo screening of probes identified 68GaPIF-3 and 68GaPIF-7 as probes with high uptake in injured lung, high uptake in injured lung versus normal lung, and high uptake in injured lung versus adjacent liver and heart tissue. A crossover, intra-animal PET/MR imaging study of 68GaPIF-3 and 68GaPIF-7 confirmed 68GaPIF-7 as the superior probe. Specificity for fibrogenesis was confirmed in a crossover, intra-animal PET/MR imaging study with 68GaPIF-7 and a non-binding control compound, 68GaPIF-Ctrl. Substituting copper-64 for gallium-68 did not affect lung uptake or specificity indicating that either isotope could be used. CONCLUSION: A series of allysine-reactive PET probes with variations in the aldehyde-reactive moiety were evaluated in a pre-clinical model of lung fibrosis. The hydrazine-bearing probe, 68GaPIF-7, exhibited the highest uptake in fibrogenic lung, low uptake in surrounding liver or heart tissue, and low lung uptake in healthy mice and should be considered for further clinical translation.
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Authors | Sergey Shuvaev, Rachel S Knipe, Matt Drummond, Nicholas J Rotile, Ilknur Ay, Jonah P Weigand-Whittier, Hua Ma, Iris Yuwen Zhou, Jesse D Roberts Jr, Katherine Black, Lida P Hariri, Yingying Ning, Peter Caravan |
Journal | Molecular imaging and biology
(Mol Imaging Biol)
Vol. 25
Issue 5
Pg. 944-953
(Oct 2023)
ISSN: 1860-2002 [Electronic] United States |
PMID | 37610609
(Publication Type: Journal Article)
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Copyright | © 2023. The Author(s), under exclusive licence to World Molecular Imaging Society. |