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J Nucl Med. 2008; 49 (Supplement 1):98P
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Radiopharmaceutical Chemistry: New Chemistry-Oncology

New Chemistry-Oncology II: Small Molecules

Orthogonal 18F and 64Cu labeling of functionalized bis(thiosemicarbazonato) complexes of copper

Laurence Carroll1, Romain Bejot1, Rebekka Hüting1, Simon Bayly1, Jonathan Dilworth1, Antony Gee2, Jérôme Declerck3 and Véronique Gouverneur1

1 Department of Chemistry, University of Oxford, Oxford, United Kingdom; 2 Clinical Imaging Centre, GSK, Hammersmith, United Kingdom; 3 Siemens Molecular Imaging, Oxford, United Kingdom


Formula

391

Objectives: A suggested mechanism of hypoxic selectivity of copper(II) bis(thiosemicarbazone) complexes (Cu-ATSM/R) proceeds via the reduction and protonation of the complexes in cells leading to irreversible dissociation and trapping of the copper. Orthogonal labeling of either the metal 64Cu or the ligand with 18F may give valuable information into the metabolic fate of the complexes in vivo.

Methods: Fluorine functionalized ligands (ATSM/PhF and ATSM/EtF) were synthesized by hydrazone coupling or Huisgen cycloaddition between a fluorinated group and either the hydrazine or propargyl functionalized bisthiosemicarbazones, and subsequently radiolabeled with 64Cu. Their 18F-labeled counterparts were synthesized by coupling of known 18F-labeled prosthetic groups (18F-4-fluorobenzaldehyde and 18F-fluoroethylazide) with the functionalized Zn complexes and further transmetalation with Cu acetate. The one-electron-reduction potentials were determined by cyclic voltammetry. Cellular uptakes and intracellular localization in HeLa cells were assessed using confocal fluorescence microscopy for Zn complexes, and radioactivity for 64Cu- and 18F-labeled ones.

Results: 64Cu- and 18F-labeled fluorinated complexes were prepared for the first time in high radiochemical purity. A quasi-reversible reduction process occurs at redox potentials similar to Cu(II)-ATSM/R derivatives. Lipophilicities (logP = 1.7-2.5) were similar to the non-fluorinated compounds. Noteworthy uptake in cells was observed.

Conclusions: Orthogonal labeling with 64Cu and 18F of Cu-ATSM/R complexes proved feasible. In vitro experiments give encouraging results to study ligand and metal biodistributions in vivo with PET.

Research Support: DTI/Siemens/GSK





This Article
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Right arrow Articles by Carroll, L.
Right arrow Articles by Gouverneur, V.
PubMed
Right arrow Articles by Carroll, L.
Right arrow Articles by Gouverneur, V.