A bis(2-pyridylmethyl) derivative of 1,4,7-triazacyclononane as highly hydrophilic chelation agent for copper


A bis(2-pyridylmethyl) derivative of 1,4,7-triazacyclononane as highly hydrophilic chelation agent for copper

Gasser, G.; Tijoe, L.; Belousoff, M. J.; Spiccia, L.; Graham, B.; Juran, S.; Walther, M.; Künstler, J.-U.; Bergmann, R.; Stephan, H.

Introduction:

Highly thermodynamically stable Cu(II) complexes are required for the development of new copper(II) target-specific radiopharmaceuticals. In this perspective, azamacrocycle derivatives [1], and in particular a 1,4,7-triazacyclononane derivative containing two pyridine pendant arms [2] is a potentially promising ligand candidate. The further addition of a carboxylic group to this chelating agent could provide an attractive lead for the labelling of biomolecules with copper radionuclides.

Experimental:

A new ligand, 2-[4,7-bis(2-pyridylmethyl)-1,4,7-triazacyclononan-1-yl]acetic acid (1), has been synthesised, and the X-ray structure of a corresponding copper(II)-complex determined. A bioconjugate (2) was obtained by coupling a modified bombesin derivative [3] to 1 (HBTU, DIPEA, DMF, r.t.). 2 was purified by semi-preparative HPLC. The free ligand 1 and the bioconjugate 2 were labelled with 64Cu. To 100 µl of ligand solution (0.0001 M ligand dissolved in 0.05 M NH4OAc), 200 kBq of 64CuCl2 was added. Labelling yields were studied by TLC.

Results and Discussion:

The structure of [1-Cu-complex]2+ was solved by X-ray single-crystal diffraction and indicates that the ligand is able to bind Cu2+ in a hexacoordinate manner. A high complex stability (logK1 > 20) was determined. The bioconjugation of 1 to a bombesin derivative was successfully achieved via amide coupling to give 2. The free ligand 1 and the bioconjugate 2 were labelled with 64Cu and the resulting complexes were found to be stable in the presence of a large excess of competing ligands such as cyclam and glutathione as well as in rat plasma. These 64Cu complexes are highly hydrophilic (logDo/w < -2.3).

Conclusion:

A bis(2-pyridylmethyl) derivative of 1,4,7-triazacyclononane 1 and its bombesin bioconjugate 2 can readily form 64Cu complexes with high stability. The bifunctional chelating agent 1 may be an attractive candidate for developing new copper radiopharmaceuticals. Preliminary biodistribution studies of 64Cu complexes of 2 are currently underway.

[1] K. P. Guerra et al., Dalton Trans., 2006, 4124-4133.
[2] G. A. McLachlan et al., Inorg. Chem. 1994, 33, 4663-4668.
[3] E. Garcia Garayoa et al., Quart. J. Nucl. Med. Molec. Imaging, 2006, 50, 15-16.

  • Poster
    17th International Symposium on Radiopharmaceutical Sciences, 30.04.-04.05.2007, Aachen, Deutschland
  • Abstract in refereed journal
    Journal of Labelled Compounds and Radiopharmaceuticals 50(2007)Suppl. 1, S230
    ISSN: 0362-4803

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