New Bispidine-Derivatives for dual-modality imaging

The diagnostic evaluation and treatment of complex diseases, like cancer, is very difficult using only standing alone methods with their individual limitations. To overcome these restrictions, a combination of different imaging modalities will be conceivable. The radionuclide based positron emission tomography (PET) and single photon emission computed tomography (SPECT) are useful for functional imaging. To obtain anatomical information, computer tomography (CT) and magnetic resonance imaging (MRI) can be used, whereas fluorescence-based optical imaging finds application in surgery guidance. [1]

Extensive research effort has shown, that 3,7-diazabicyclo[3.3.1]nonane-derivatives (bispidines) built up thermodynamic and kinetic very stable complexes with copper(II) ions (logK = 16.28) [2]. Different functional groups of the backbone (hydroxyl and carboxyl groups) provide the opportunity for simultaneous attachment of dyes and biomolecules (e. g. peptides, proteins, antibodies) as vector molecules. After that functionalization, the complexation of radioactive copper isotopes (⁶¹Cu, ⁶⁴Cu, ⁶⁷Cu) allows visualization of cancer tissue with PET and radiotherapy.

The hydroxyl group at C9 was functionalized using nitrophenyl chloroformate for active ester generation. Therefore, a fluorescence label could be coupled to the bispidine by urethane bond formation.

We will report about the versatility of bispidines as compounds to realize different functionalities in one molecule. The synthesis and characterization of such derivatives, and radiolabeling experiments with the PET-radionuclide 64Cu will be discussed.

[1] Kuil, J., Velders, A. H., van Leeuwen, F. W. B.; Bioconjugate Chem. 2010, 21, 1709-1719.
[2] Juran, S., Walther, M., Stephan, H., Bergmann, R., Steinbach, J., Kraus, W., Emmerling, F., Comba, P.; Bioconjugate Chem. 2009, 20, 347-359.