Novel Multidentate Bifunctional Chelating Agents for the Development of Zirconium-89 Based Molecular Imaging Probes
Swiss National Science Foundation Grant N° 205321–157216
Principle Investigators: Prof. Dr. Thomas L. Mindt (LBIAD), Prof. Dr. Gilles Gasser (Chimie ParisTech)
Zirconium-89 (89Zr) based radiotracers hold great promise as immuno-PET imaging agents in nuclear medicine (PET = positron emission tomography). However, insufficient stability of currently used radiometal complexes in vivo is a safety concern for clinical applications. We have developed a novel bifunctional, octadentate chelator (termed DFO*), which provides 89Zr-labelled immuno-conjugates of remarkably improved stability in vitro and in vivo. We are currently investigating further optimization of the new scaffold DFO* and its application for the development of a range of metal-based radiopharmaceuticals.
DFT optimized structure of Zr-DFO* (atom colour coding: white = carbon; blue = nitrogen; red = oxygen; magenta = zirconium); hydrogen atoms are omitted for clarity.
 “An Octadentate Bifunctional Chelating Agent for the Development of Stable Zirconium-89 Based Molecular Imaging Probes” M. Patra, A. Bauman, C. Mari, C. A. Fischer, O. Blacque, D. Häussinger, G. Gasser, T. L. Mindt Chemical Communications 2014, 50, 11523-11525.
 “Comparison of the Octadentate Bifunctional Chelator DFO*-pPhe-NCS and the Clinically Used Hexadentate Bifunctional Chelator DFO-pPhe-NCS for 89Zr-Immuno-PET” D. J. Vugts, C. Klaver, C. Sewing, A. J. Poot, K. Adamzek, S. Huegli, C. Mari, I. E. Valverde, G. Gasser, T. L. Mindt, G.A.M.S. van Dongen European Journal of Nuclear Medicine and Molecular Imaging 2017, 44, 286-295.
 “A Solid Phase-Assisted Approach for the Facile Synthesis of a Highly Water Soluble Octadentate Zirconium-89 Chelator for Radiopharmaceutical Development” M. Briand, M. Aulsebrook, T. L. Mindt, G. Gasser, Dalton Transactions 2017, 46, 6387-1638
Metabolically Stabilized Peptidomimetics for Improved Tumour Targeting
Austrian Science Fund Grant N° P 31477-B28
Principle Investigator: Prof. Dr. Thomas L. Mindt (LBIAD, Vienna)
Co-Investigators: Prof. Markus Mitterhauser (LBIAD, Vienna), Dr. Wolfgang Kandioller (University of Vienna), Dr. Berthold Nock (Demokritos, Athens)
Regulatory peptides are a class of biomolecules with ideal characteristics for the development of tumour-targeting radiopharmaceuticals. They exhibit a high, specific accumulation in tumours but not in healthy tissue and a favourable pharmacokinetic profile. A drawback of using such peptides for the selective delivery of attached radionuclides to tumours is their low stability due to rapid degradation by enzymes (proteases) before they can reach their target (tumours). It is known from the literature that enhancing the metabolic stability of a peptide carrier can substantially increase its uptake in tumours and metastases. Despite considerable research efforts directed towards the stabilization of the peptides without influencing their favourable biological characteristics, no general approach has yet been identified. We have recently introduced a novel “click chemistry” methodology to achieve this goal. We use metabolically stable 1,2,3-triazole heterocycles as biosiosteres of labile amide bonds of the peptides. We were able to show that the obtained, radiolabelled peptidomimetics exhibit an increased stability and, as a result, a significantly improved tumour uptake in mice.
The introduction of 1,2,3-triazoles as metabolically stable bioisosteres of amide bonds results in radiolabelled peptidomimetics with improved tumour-targeting properties.
 “1,2,3-Triazoles as Amide Bond Mimics: Triazole Scan Yields Protease-Resistant Peptidomimetics for Tumor Targeting” I. E. Valverde, A. Bauman, C. A. Kluba, S. Vomstein, M. Walter, T. L. Mindt Angewandte Chemie International Edition, 2013, 52, 8957-8960.
 “1,2,3-Triazole Stabilized Neurotensin-Based Radiopeptidomimetics for Improved Tumor Targeting” A. Mascarin, I. E. Valverde, S. Vomstein, T. L. Mindt Bioconjugate Chemistry 2015; 26, 2143–2152.