Bispidine ligands for the potential application in nuclear medicine

Objectives
An important part of radiopharmaceuticals containing radiometals is the so-called bifunctional chelator (BFC). Bispidine ligands (3,7-diazabicyclo[3.3.1]nonane) (see Figure 1) developed in the Comba group are perfectly suited BFCs for the application in nuclear medicine. Due to their preorganisation and rigidity of the backbone with the donor atoms N3 and N7 they generally form complexes fastly and with high stability.[1]
Methods
By choosing suitable moieties at position R1 and R2 and by fine tuning of the pyridyl groups at C2 and C4,[2] bispidines can be tailored for the complexation of many different metal ions. Coupling to vector entities is performed at the ester groups at C1/5 or the hydroxyl group at C9.[3-4] One of the applications for bispidine ligands is 64CuII PET imaging (positron emission tomography).[3,5] We design bispidine ligand systems for PET and evaluate their potential in radiolabeling experiments and stability studies.
Results
First in vitro and in vivo studies show the high potential of the bispidine chelators for PET application.[3] The hexadentate ligands N2Py4, N2Py3Pdz and the isomers Hbispa1a/b with pyridyl, pyridazyl or picolinic acid groups at R1 and/or R2 (see Figure 1) are promising BFCs for 64CuII PET imaging.[6-7]
Conclusions
The hexadentate ligands shown in Figure 1 and derivatives are further investigated regarding the application in nuclear medicine.
References
[1] P. Comba, M. Kerscher, W. Schiek, Prog Inorg Chem 2007, 55, 613-704.
[2] P. Comba, S. Hunoldt, M. Morgen, J. Pietzsch, H. Stephan, H. Wadepohl, Inorg Chem 2013, 52, 8131-8143.
[3] S. Juran, M. Walther, H. Stephan, R. Bergmann, J. Steinbach, W. Kraus, F. Emmerling, P. Comba, Bioconjugate Chem 2009, 20, 347-359.
[4] H. Stephan, M. Walther, S. Fahnemann, P. Ceroni, J. K. Molloy, G. Bergamini, F. Heisig, C. E. Muller, W. Kraus, P. Comba, Chem-Eur J 2014, 20, 17011-17018.
[5] A. Roux, A. M. Nonat, J. Brandel, V. Hubscher-Bruder, L. J. Charbonniere, Inorg Chem 2015, 54, 4431-4444.
[6] C. Bleiholder, H. Borzel, P. Comba, R. Ferrari, M. Heydt, M. Kerscher, S. Kuwata, G. Laurenczy, G. A. Lawrance, A. Lienke, B. Martin, M. Merz, B. Nuber, H. Pritzkow, Inorg Chem 2005, 44, 8145-8155.
[7] P. Comba, L. Grimm, C. Orvig, K. Rück, H. Wadepohl, Inorg Chem 2016, manuscript accepted.