1. Bifunctional (64)Cu-labelled macrobicyclic cage amine isothiocyanates for immuno-positron emission tomography.
- Author
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Paterson BM, Buncic G, McInnes LE, Roselt P, Cullinane C, Binns DS, Jeffery CM, Price RI, Hicks RJ, and Donnelly PS
- Subjects
- Animals, Cell Line, Tumor, Chelating Agents chemistry, Drug Stability, Humans, Isotope Labeling, Magnesium chemistry, Mammary Neoplasms, Experimental diagnostic imaging, Mammary Neoplasms, Experimental metabolism, Mice, Receptor, ErbB-2 metabolism, Trastuzumab chemistry, Amines chemistry, Copper Radioisotopes, Immunoconjugates chemistry, Immunoconjugates pharmacokinetics, Isothiocyanates chemistry, Macrocyclic Compounds chemistry, Positron-Emission Tomography methods
- Abstract
New macrobicyclic cage amine or "sarcophagine" (sar) bifunctional chelators have been synthesised that form copper complexes of exceptional in vivo stability and incorporate isothiocyanate (-NCS) functional groups for conjugation to an antibody. The chelators were synthesised from the methyl-capped complex [Mg(II)(CH3)(NH2)sar](2+). Coordination of Mg(II) within the cavity of the cage amine ligand protects the secondary amine atoms from reacting with the -NCS functional groups. Two different [Mg(II)(NCS-sar)](2+) derivatives were conjugated to the HER2/neu-targeting antibody trastuzumab and the progress of the reaction monitored by electrospray mass spectrometry. The Mg(II) ion was removed from the immunoconjugates under mild conditions (0.1 M citrate buffer, pH 6). Labelling of the (CH3)(p-NCS-Ph)sar-trastuzumab conjugate with (64)Cu(II), a radioisotope suitable for positron emission tomography (PET), was fast (∼5 min) and easily performed at room temperature with high radiochemical purity (>95%). Biodistribution and PET imaging studies in vivo showed that (64)Cu-labelled (CH3)(p-NCS-Ph)sar-trastuzumab maintained high stability under physiological conditions with high and selective uptake in a HER2-positive cancer cell line. The stability of the copper complex and the 12.7 h half-life of the radioisotope allows clear visualisation of tumours out to 48 h.
- Published
- 2015
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