simplifying the preparation of 18 f-based biomolecular imaging agents through ‘click’ chemistry
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
James Inkster, Msc., SFU/TRIUMF
Simplifying the Preparation of 18F-based Biomolecular Imaging Agents Through ‘Click’
Chemistry
CANADA’S NATIONAL LABORATORY FOR PARTICLE AND NUCLEAR PHYSICSOwned and operated as a joint venture by a consortium of Canadian universities via a contribution through the National Research Council Canada
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
N
O
18F
Biomolecules as molecular imaging agents
Why biomolecules? Established synthetic procedures Exquisite specificity
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
Direct labelling
"Pre"- labelling
"Post"- labelling
radionuclide
smallmolecule(prostheticgroup)
biomolecule(targeting
agent)
‘Click’ is a concept
Kolb, H.C. & Sharpless, K.B. Drug Discovery Today 2003, 8, 1128-1137.
1,2,3- triazoles
epoxide ring openings
oximes
hydrazones
N
HN
NH
OH
NO
NN
N
[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
N
O
18FN
O
N -OTf DMSO110 oC, 15 min
K[18F]F-K222
[18F]FPy5yne
Inkster, J. A. H. et al. Journal of Labelled Compounds and Radiopharmaceuticals 2008, 51, 444-452.
A typical radioTLC
Radiochemical Yield:89.6%±2.0% (n=4)
18F-
N
O
18F
Peptide labelling with [18F]FPy5yne
N3
O
HN
O
OH
NH
NH2
O
HN
O
NH
NH
HNNH2
O
OH
BG142
[18/19F]FPy5yneCu(ACN)4PF6TBTA
N
O
HN
O
OH
NH
NH2
O
HN
O
NH
NH
HNNH2
O
OH
NN
NF
18/19F-BG142
O
2:1 PBS (pH 7.2): DMF
Co-injections: (A) [18F]FPy5yne
(B) 18F-Peptide
RCY = 89.6%±2.0% (n =4)(A) (B)
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 Medicine 2002, 29, 855.
Same Prosthetic Group, Different Biomolecule
P
O
OHO
OHN DNA 20mer
O
N3
P
O
OHO
OHN DNA 20mer
O
N
NNO
N F
[18/19F]FPy5yneCuBrTBTA
2,6-lutidine
4:1 PBS:DMF
N3-ODN1
18/19F-ODN1
Why make radioactive DNA?
Robinson, R. PLoS Biology, 2004, 2, 18-20.
“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 Science 2008, 14, 455-460.
Juliano, R. et al. Nucleic Acids Research 2008, 36, 4158-4171.
Debart, F. et al. Current Topics in Medicinal Chemistry 2007, 7, 727-737.
Conclusion & Acknowledgements
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