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Simplifying the Preparation of 18 F-based Biomolecular Imaging Agents Through ‘Click’ Chemistry

CANADA’S NATIONAL LABORATORY FOR PARTICLE AND NUCLEAR PHYSICS. Owned and operated as a joint venture by a consortium of Canadian universities via a contribution through the National Research Council Canada.

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Simplifying the Preparation of 18 F-based Biomolecular Imaging Agents Through ‘Click’ Chemistry

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  1. CANADA’S NATIONAL LABORATORY FOR PARTICLE AND NUCLEAR PHYSICS Owned and operated as a joint venture by a consortium of Canadian universities via a contribution through the National Research Council Canada Simplifying the Preparation of 18F-based Biomolecular Imaging Agents Through ‘Click’ Chemistry James Inkster, Msc., SFU/TRIUMF LABORATOIRE NATIONAL CANADIEN POUR LA RECHERCHE EN PHYSIQUE NUCLÉAIRE ET EN PHYSIQUE DES PARTICULES Propriété d’un consortium d’universités canadiennes, géré en co-entreprise à partir d’une contribution administrée par le Conseil national de recherches Canada

  2. Biomolecules as molecular imaging agents • Why biomolecules? • Established synthetic procedures • Exquisite specificity

  3. Biomolecules as molecular imaging agents • Why biomolecules? • Established synthetic procedures • Exquisite specificity • Why not? • Often requires a complex radiosynthesis • Certain species may have issues with in vivo stability, bioavailability • Most biomolecules are incompatible with many radiolabelling protocols

  4. ‘Click’ is a concept oximes 1,2,3- triazoles hydrazones epoxide ring openings Kolb, H.C. & Sharpless, K.B. Drug Discovery Today2003, 8, 1128-1137.

  5. [18F]FPy5yne: an optimized 18F- based bifunctional molecule • Efficient incorporation of [18F]fluoride via 2-substitued pyridinyl nucleophilic heteroaromatic substitution • Efficient bioconjugation via Huisgen [3+2] cycloaddition reaction Inkster, J. A. H. et al. Journal of Labelled Compounds and Radiopharmaceuticals2008, 51, 444-452.

  6. A typical radioTLC Radiochemical Yield: 89.6%±2.0% (n=4) 18F-

  7. Peptide labelling with [18F]FPy5yne

  8. Co-injections: (A) [18F]FPy5yne (B) 18F-Peptide (A) RCY = 89.6%±2.0% (n =4) (B)

  9. Proposed biological applications i.e. Where are we going with all this? • 18F-BBN [18F-bombesin(7-14)] • GRP receptors expressed in ~65% breast cancers* • 18F analogs of bombesin have been prepared • 18F-BVD15 • NPY1 receptors expressed in 58%-85% breast cancers* • Attractive target, not yet labelled with 18F • 18F-Senktide (a NK-3 receptor agonist) • Neuropeptide analog of substance P *Reubi J.C. European Journal of Nuclear Medicine2002, 29, 855.

  10. Same Prosthetic Group, Different Biomolecule

  11. Why make radioactive DNA? Robinson, R. PLoS Biology, 2004, 2, 18-20.

  12. “I’ve seen the future, brother: it is murder.”–L.Cohen • The challenge: the in vivo delivery of nucleic-acid based radiotracers into target cells, followed by retention of the probe by an antisense mechanism Abes, R. et al., Journal of Peptide Science2008, 14, 455-460. Juliano, R. et al. Nucleic Acids Research2008, 36, 4158-4171. Debart, F. et al. Current Topics in Medicinal Chemistry2007, 7, 727-737.

  13. The goal: to employ TRIUMF LS’s expertise in synthetic organic and radiochemistry to develop simple, efficient and high-impact protocols for the preparation of biological radiopharmaceuticals The Team PET Group (TRIUMF) Tim Storr (SFU) Mike Adam (UBC/TRIUMF) David Perrin (UBC) François Bernard (BC Cancer) Brigitte Guérin (U. de Sherbrooke) Tom Ruth Conclusion & Acknowledgements

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