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In Vitro and In Vivo Evaluations of a Hydrophilic ⁶⁴Cu-Bis(Thiosemicarbazonato)–Glucose Conjugate for Hypoxia Imaging

¹ Siemens Oxford Molecular Imaging Laboratory, Inorganic Chemistry Laboratory, University of Oxford, Oxford, United Kingdom; ² Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom; ³ CRUK/MRC, Gray Institute for Radiation Oncology and Biology, University of Oxford, Headington, Oxford, United Kingdom; and ⁴ The Wolfson Brain Imaging Centre, Addenbrooke's Hospital, Cambridge, United Kingdom

Correspondence: For correspondence or reprints contact: Martin Christlieb, Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Bldg., Old Road Campus, Headington, Oxford OX3 7DQ, United Kingdom. E-mail: martin.christlieb{at}rob.ox.ac.uk

A water-soluble glucose conjugate of the hypoxia tracer ⁶⁴Cu-diacetyl-bis(N⁴-methylthiosemicarbazone) (⁶⁴Cu-ATSM) was synthesized and radiolabeled (⁶⁴Cu-ATSE/A-G). Here we report our initial biological experiments with ⁶⁴Cu-ATSE/A-G and compare the results with those obtained for ⁶⁴Cu-ATSM and ¹⁸F-FDG. Methods: The uptake of ⁶⁴Cu-ATSE/A-G and ⁶⁴Cu-ATSM into HeLa cells in vitro was investigated at a range of dissolved oxygen concentrations representing normoxia, hypoxia, and anoxia. Small-animal PET with ⁶⁴Cu-ATSE/A-G was performed in male BDIX rats implanted with P22 syngeneic carcinosarcomas. Images of ⁶⁴Cu-ATSM and ¹⁸F-FDG were obtained in the same model for comparison. Results: ⁶⁴CuATSE/A-G showed oxygen concentration–dependent uptake in vitro and, under anoxic conditions, showed slightly lower levels of cellular uptake than ⁶⁴Cu-ATSM; uptake levels under hypoxic conditions were also lower. Whereas the normoxic uptake of ⁶⁴Cu-ATSM increased linearly over time, ⁶⁴Cu-ATSE/A-G uptake remained at low levels over the entire time course. In the PET study, ⁶⁴CuATSE/A-G showed good tumor uptake and a biodistribution pattern substantially different from that of each of the controls. In marked contrast to the findings for ⁶⁴Cu-ATSM, renal clearance and accumulation in the bladder were observed. ⁶⁴Cu-ATSE/A-G did not display the characteristic brain and heart uptake of ¹⁸F-FDG. Conclusion: The in vitro cell uptake studies demonstrated that ⁶⁴Cu-ATSE/A-G retained hypoxia selectivity and had improved characteristics when compared with ⁶⁴Cu-ATSM. The in vivo PET results indicated a difference in the excretion pathways, with a shift from primarily hepatointestinal for ⁶⁴Cu-ATSM to partially renal with ⁶⁴Cu-ATSE/A-G. This finding is consistent with the hydrophilic nature of the glucose conjugate. A comparison with ¹⁸F-FDG PET results revealed that ⁶⁴Cu-ATSE/A-G was not a surrogate for glucose metabolism. We have demonstrated that our method for the modification of Cu-bis(thiosemicarbazonato) complexes allows their biodistribution to be modified without negating their hypoxia selectivity or tumor uptake properties.

Key Words: PET • molecular imaging • ⁶⁴Cu-ATSM • hypoxia • biodistribution

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JNM 2008 49: 11A-12A. [Full Text]