Past Funded Projects

Novel Multidentate Bifunctional Chelating Agents for the Development of Zirconium-89 Based Molecular Imaging Probes

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*),[1] which provides 89Zr-labelled immuno-conjugates of remarkably improved stability in vitro and in vivo.[2] 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.

[1] “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 201450, 11523-11525.
[2] “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 201744, 286-295.
[3] “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 201746, 6387-1638

Swiss National Science Foundation Grant N° 205321–157216

Principle Investigator
Prof. Dr. Thomas L. Mindt

Prof. Dr. Gilles Gasser (Chimie ParisTech, formerly at University of Zurich)

Funding: kEUR 406

Duration: 2018 – 2023

Radiolabelled Peptides for the Imaging of the PD-L1 Receptor

Inhibiting the interaction between the immune checkpoint PD-1 and its ligand PD-L1 activates the immune system to fight cancer. Detection of the expression of PD-L1 is a prerequisite for immune checkpoint inhibition therapy. In this project, we focus our efforts towards the development of a PD-L1 specific nuclear imaging probe based on a peptides.

Selected Publications
“Evaluation of a Macrocyclic Peptide as Potential PET Imaging Probe for PD-L1” N. Jouini, J. Cardinale, T. L. Mindt ChemMedChem2022, 17, E202200091

Ludwig Boltzmann Society (2018-2021), Austria

Principle Investigator
Prof. Dr. Thomas L. Mindt

Metabolically Stabilized Triazolo-Peptidomimetics for Improved Tumor-Targeting

Labile amide bonds in peptides can be replaced by triazoles to enhance their metabolic stability and tumor uptake in vivo.

A: 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres of trans amide bonds. B: 1,5-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres of cis amide bonds.

Replacement of amide bonds in the backbone of peptides by 1,2,3-triazole heterocycles increases the metabolic stability and tumor-uptake of peptide-based radiotracers (see also current funded projects).
We have applied this amide-to-triazole switch methodology to several radiolabeled, tumor-targeting peptides including bombesin, neurotensin, minigastrin and other peptides. In all cases, a triazole-scan (systematic replacement of each single amide bond) yielded triazolo-peptidomimetics with improved blood serum stability, maintained biological properties and enhanced tumor-uptake in mice bearing tumor xenografts. In most cases, multiple replacements of amide bonds with triazoles was possible without impairment of the peptide´s biological function.
The amide-to-triazole switch methodology is fully compatible with efficient manual and automated solid phase peptide synthesis.

Selected Publications:                       –

  1. “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
  2. “Probing the Backbone Function of a Bombesin-Based Radiotracer by an Amide-to-Triazole Substitution Strategy” I. E. Valverde, S. Vomstein, T. L. Mindt Journal of Medicinal Chemistry 2015, 58, 7475–7484
  3. “Radiolabeled Analogs of Neurotensin (8-13) Containing Multiple 1,2,3-Triazoles as Stable Amide Bond Mimics in the Backbone” A. Mascarin, I. E. Valverde, T. L. Mindt Medicinal Chemical Communications 2016, 7, 1640-1646
  4. “Amide-to-Triazole Switch vs. In Vivo NEP-Inhibition Approaches to Promote Radiopeptide Targeting of GRPR-Positive Tumors” T. Maina, A. Kaloudi, I. E. Valverde, T. L. Mindt, B. A. Nock Nuclear Medicine and Biology 2017, 52, 57-62
  5. “Design of Radiolabeled Minigastrin Analogs by Multiple Amide-to-Triazole Substitutions for Enhanced Tumor Targeting” N. M. Grob, S. Schmid, R. Schibli, M. Béhé, T. L. Mindt Journal of Medicinal Chemistry 2020, 63, 4496-4505
  6. “1,4-Disubstituted 1,2,3-Triazoles as Amide Bond Surrogate for the Stabilisation of Linear Peptides with Biological Activity” L. M. Recnik, W. Kandioller, T. L. Mindt Molecules 2020, 25, 3576-3602
  7. “Single Peptide Backbone Surrogate Mutations to Regulate GPCR Subtype Selectivity” E. I. Vrettos, I. E. Valverde, A. Mascarin, P. N. Pallier, M. Fragai, G. Parigi, B. Hirmiz, N. Bekas, N. M. Grob, E. Stylos, M. Del Borgo, M.-I. Aguilar, F. Magnani, N. Syed, T. Crook, E. Waqif, E. Ghazaly, R. E. Widdop, C. Luchinat, A. T. Michael-Titus, T. L. Mindt, A. G. Tzakos Chemistry – A European Journal 2020, 26, 10690

– Swiss National Science Foundation (2011-2019), grant No 205321_132280/1 and 2021_157076/1
– Austrian Science Fund (2018-2023) grant No P31477-B28

Principle Investigator
Prof. Dr. Thomas L. Mindt

Click-to-Chelate: An Efficient Approach for 99mTc-Radiolabeling and the Preparation of Multifunctional Radioconjugates

Click-to-Chelate Approach
Multifunctional Radioconjugates

The click-to-chelate approach provides an efficient and versatile strategy for the radiolabeling of biomolecules with the 99mTc-tricarbonyl core as well as other radionuclides. In addition, this methodology utilizes orthogonal chemistry that enable the rapid and straight-forward assembly of multifunctional radioconjugates for various applications.

Selected Publications

  1. “Click to Chelate: Synthesis and Installation of Metal Chelates into Biomolecules in a Single Step” T. L. Mindt, H. Struthers, L. Brans, T. Anguelov, C. Schweinsberg, V. Maes, D. Tourwé, and R. Schibli Journal of the American Chemical Society 2006, 128, 15096
  2. “Click Chemistry Radiosynthesis and Preclinical Evaluation of a New 18F-Labelled Folic Acid Derivative” T. L. Ross, M. Honer, P. Y. H. Lam, T. L. Mindt, V. Groehn, R. Schibli, P. A. Schubiger, S. M. Ametamey Bioconjugate Chemistry 2008, 19, 2462
  3. “A Click Approach to Structurally Diverse Conjugates Containing a Central Di-1,2,3-Triazole Metal Chelate” T. L. Mindt, C. Schweinsberg, L. Brans, A. Hagenbach, U. Abram, D. Tourwé, E. Garcia-Garayoa,R. Schibli ChemMedChem 2009, 4, 529
  4.  “Molecular Assembly of Multifunctional Tc-99m Radiopharmaceuticals using “Clickable” Amino Acid Derivatives“ T. L. Mindt, H. Struthers, B. Spingler, L. Brans, D. Tourwe, E. Garcia-Garayoa, R. Schibli ChemMedChem 2010, 5, 2026-2038
  5. „Imaging of Activated Macrophages in Experimental Osteoarthritis Using Folate Targeted Animal SPECT/CT“ T. M. Piscaer, C. Müller, T. L. Mindt, E. Lubberts,J. A. N. Verhaar,E. P. Krenning, R. Schibli,M. De Jong, H. Weinans Arthritis & Rheumatism 2011, 63, 1898–1907
  6. “Click-to-Chelate: Development of Technetium- and Rhenium-Tricarbonyl Labeled Radiopharmaceuticals” C. A. Kluba, T. L. Mindt Molecules 2013, 18, 3206-3226
  7.  “A Bombesin-Shepherdin Radioconjugate Designed for Combined Extra- and Intracellular Targeting” C. A. Fischer, S. Vomstein, T. L. Mindt Pharmaceuticals 2014, 7, 662-675
  8.  “Sorbitol as a Polar Pharmacological Modifier to Enhance the Hydrophilicity of 99mTc-Tricarbonyl-Based Radiopharmaceuticals” C. Giammei, T. Balber, K. Bencurova, J. Cardinale, N. Berroterán-Infante, M. Brandt, N. Jouini, M. Hacker, M. Mitterhauser and T. L. Mindt Molecules 2020, 25, 2680-2694

ETH Zurich (2005-2009) and University of Basel (2009-2014), Switzerland

Principle Investigator
Prof. Dr. Thomas L. Mindt