Conférence du Professeur David Perrin (UBC)

Titre: Using Boron to Label Peptides with ¹⁸F for Functional Cancer Imaging: The Quest for Kinetic Stability.

Cette conférence sera prononcée par le professeur David Perrin du Département de chimie de l'University of British Columbia. Ce dernier sera à Montréal à titre d'examinateur externe d'une soutenance de thèse en chimie.

Résumé : By providing high spatial and temporal resolution in vivo images, PET imaging will help us realize the promise of personalized molecular medicine. Whereas the various nuclear properties make F18 a choice PET isotope, the chemical properties of fluoride complicate its use in biomolecular labelling such that 2-4 'hot' steps are required. Given the relatively short half-life of F18 (110 minutes), a rapid 1-step, reproducible, clean, and high yielding aqueous labelling of an intact biomolecule would be desirable. We hypothesized that biomolecules could be labelled via a pendent boronic ester in a single aqueous step whereby chemoselective F18-capture gives an in vivo stable F18-labeled aryltrifluoroborate. While the B-F bond is considered to be one of the strongest single bonds on the periodic table, we used ¹⁹F-NMR and radioactive ¹⁸F-¹⁹F isotopic exchange assays to demonstrate that the B-F bond can be surprisingly labile, yet tuneable through chemical synthesis for applications in PET. Our findings have mechanistic implications for metal-mediated cross couplings and provide a rubric for developing a new class of boron reagents for expeditious PET ¹⁸F-labeling. Hence, we labelled the drug Marimastat, a potent MMP (matrix metalloprotease) inhibitor to provide the first images of MMP activity in metastatic breast cancer xenografts.  This approach now works with LLP2A, RGD, diamino-acid ureas, folic acid, oligos, and biotin, all of which are important imaging agents. Click reactions are also possible and taken together these results suggests that boron represents a viable platform for labelling most large biomolecules. Our talk will start with fundamental results obtained to understand the aqueous stability of aryltrifluoroborates. These results then guided the synthetic design of substructures for use in PET imaging. Our talk will end with in vivo PET images of cancer in mice

Information supplémentaire