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Neue Multidentate Bifunktionelle Chelator Systeme für die Entwicklung von Zirkonium-89 Basierenden Molekularen Bildgebungsproben

English title Novel Multidentate Bifunctional Chelating Agents for the Development of Zirconium-89 Based Molecular Imaging Probes
Applicant Gasser Gilles
Number 157216
Funding scheme Project funding (Div. I-III)
Research institution Chimie ParisTech PSL Research University
Institution of higher education University of Zurich - ZH
Main discipline Inorganic Chemistry
Start/End 01.05.2015 - 31.12.2019
Approved amount 350'000.00
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All Disciplines (3)

Discipline
Inorganic Chemistry
Pharmacology, Pharmacy
Organic Chemistry

Keywords (5)

immuno-PET; PET imaging; Zirconium-89; radiometal chelators; cancer diagnosis

Lay Summary (French)

Lead
Le but de ce projet est de synthétiser de nouveaux chélateurs octadentates linéaires ou cycliques qui pourront être conjugués à des molécules d’importance biologique comme des peptides, des nanoparticules ou des anticorps and ensuite radiomarqués avec du 89Zr. Les propriétés physico-chimiques de tous les nouveaux conjugués radioactifs seront étudiées in vitro et in vivo et comparées avec celles des conjugués analogues dérivés du DFO. Nous espérons que ce projet permettra de découvrir de nouveaux chélateurs efficaces en médicine nucléaire.
Lay summary
Le radionucléide Zirconium-89 (89Zr) est un nouveau radionucléide métallique très prometteur pour des applications diagnostiques en tomoscintigraphie par émission de positrons (TEP) haute résolution. Le temps de demi-vie du 89Zr (t½ = 78.4 h) correspond très bien avec le temps de demi-vie biologique d’anticorps. Ainsi, leur combinaison en TEP immunologique présente de très grandes promesses. Plusieurs études cliniques ont ainsi démontré le potentiel d’anticorps marqués au 89Zr. Néanmoins, le plus grand obstacle dans l’utilisation du 89Zr pour le diagnostic de certaines maladies est le manque de méthodes pour former des chélates stables de 89Zr. Pour le moment, seul des dérivatives du desferrioxamine (DFO) sont utilisés malgré qu’il y ait des preuves du manque de stabilité de ces composés in vivo. En effet, des études sur des souris ont montré une accumulation du 89Zr dans les os. Ceci est très préoccupant et démontre très clairement qu’il est important de développer de nouveaux chélateurs pour 89Zr qui sont plus stables que le DFO. Récemment, nos groupes de recherche à Zurich et Bâle pu montrer qu’un chélateur octadentate qui comprend quatre unités hydroxymate (nous avons appelé ce nouveau chélateur DFO*) a des meilleures propriétés chélatrices que le DFO qui est un chélateur hexadentate.
Le but de ce projet est de synthétiser de nouveaux chélateurs octadentates linéaires ou cycliques qui pourront être conjugués à des molécules d’importance biologique comme des peptides, des nanoparticules ou des anticorps and ensuite radiomarqués avec du 89Zr. Les propriétés physico-chimiques de tous les nouveaux conjugués radioactifs seront étudiées in vitro et in vivo et comparées avec celles des conjugués analogues dérivés du DFO. Nous espérons que ce projet permettra de découvrir de nouveaux chélateurs efficaces en médicine nucléaire.

Direct link to Lay Summary Last update: 19.01.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
An Overview of PET Radiochemistry, Part 2: Radiometals
Brandt Marie, Cardinale Jens, Aulsebrook Margaret L., Gasser Gilles, Mindt Thomas L. (2018), An Overview of PET Radiochemistry, Part 2: Radiometals, in Journal of Nuclear Medicine, 59(10), 1500-1506.
A solid phase-assisted approach for the facile synthesis of a highly water-soluble zirconium-89 chelator for radiopharmaceutical development
Briand Manon, Aulsebrook Margaret L., Mindt Thomas L., Gasser Gilles (2017), A solid phase-assisted approach for the facile synthesis of a highly water-soluble zirconium-89 chelator for radiopharmaceutical development, in Dalton Transactions, 46(47), 16387-16389.
Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET
Danielle Vugts, Chris Klaver, Claudia Sewing, Alex Poot, Kevin Adamzek, Sereina Huegli, Cristina Mari, Gerard Visser, Ibai Valverde, Gilles Gasser, Thomas Mindt, Guus van Dongen (2017), Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET, in Eur. J. Nucl. Med. Mol. Imaging, 44, 286-295.

Collaboration

Group / person Country
Types of collaboration
Novartis, Basel Switzerland (Europe)
- Research Infrastructure
PD Dr. Bernhard Spingler, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Guus van Donggen Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
ETH Zurich Switzerland (Europe)
- Research Infrastructure
Dr. Olivier Blacque, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Departement Chemie, University of Basel Switzerland (Europe)
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
2nd Medical Imaging Cluster Festival Poster N/A 06.06.2019 Vienna, Austria Mindt Thomas;
Ludwig Boltzmann Society Meeting for Health Sciences Poster N/A 29.11.2018 Vienna, Austria Mindt Thomas;
2nd Donau Symposium & 3rd CBmed Biomarker Conference Poster N/A 14.03.2018 Vienna, Austria Mindt Thomas;


Awards

Title Year
Eur. J. Nucl. Med. Mol. Imag. Best Article Award of 2017 2019
Poster Award Bronze 2019
EuroBIC Medal Award for work in Bioinorganic Chemistry. 2018
2016 Thieme Chemistry Journal Award. 2016
Ernest Th. Jucker Prize from the Ernest Th. Jucker Foundation for research against cancer. 2016
Werner Prize from the Swiss Chemical Society for outstanding independent chemical research. 2015

Abstract

Background: The radionuclide Zirconium-89 (89Zr) is an emerging new metallic radionuclide with promising characteristics for application in high resolution PET (positron emission tomography) diagnosis in the field of nuclear medicine. The physical half-life of 89Zr (t½ = 78.4 h) matches well the biological half-life of antibodies (Abs) and thus, their combination in immuno-PET agents shows great promise because optimal tumour to non-tumour ratios important for imaging at late time points can be achieved. Several preclinical studies and clinical trials have demonstrated the potential of 89Zr-based radiopharmaceuticals, in particular 89Zr-labeled Abs. A major limitation of the use of 89Zr for immuno-PET imaging is the lack of appropriate methods for the stable chelation of the 89Zr radionuclide. To date, the 89Zr labelling of Abs is obtained exclusively through derivatives of desferrioxamine (DFO). The use of DFO as a chelator is very attractive since it has been safely used in the clinic for many years for the treatment of acute iron poisoning. However, the production of 89Zr-DFO coupled antibodies is quite challenging and there is evidence that some 89Zr is released from the chelator in vivo and taken up in the bones of mice. The potential release of radioactive 89Zr in vivo and accumulation in radiation sensitive bones is a safety concern and the search for better chelators for zirconium is therefore highly desirable. Our groups and others are currently investigating more stable alternatives to DFO.Working hypothesis: We hypothesize (or have partly already shown - see preliminary results) that complexes of 89Zr with octadentate chelator systems comprising four hydroxamate units will exhibit improved properties for biological applications in comparison the analogous desferrioxamine (DFO), a currently used hexadentate chelating system. Application of the new chelators in 89Zr immuno-PET in vivo will significantly reduce unspecific uptake of radioactivity in radiation sensitive bones as the result of the improved stability of the 89Zr complexes which prevents the release of the radiometal from the chelate. By preventing/reducing unnecessary radiation burden to patients, the novel PET agents will display an improved safety profile for clinical applications. Specific aims: We will synthesize a series of novel, linear and/or cyclic octadentate bifunctional chelating agents for conjugation to molecules of biological importance (e.g., antibodies, peptides) and radiolabeling of the conjugates with the PET isotope 89Zr. The physico-chemical properties of radioconjugates will be investigated in vitro and in vivo in direct comparison with analogous conjugates that are derivatized with the currently common DFO ligand system.Objectives: The overall objective of this research proposal is to provide the communities involved in radio-pharmaceutical and nuclear medicinal research with new bifunctional chelating agents (BFCA) for the development of PET radiodiagnostics with improved properties. Subproject A: Guided by DFT calculations, novel octadentate, linear and cyclic BFCA comprising four hydroxamate functionalities will be synthesized. In addition, the chelators will be modified with polar moieties (e.g., short ethylene glycol units) to improve solubility. Complex formation with non-radioactive metals (e.g., natZr, natGa) will be studied. Subproject B: The novel BFCA will be conjugated to an Ab (e.g., Herceptin) and peptides (e,g,, bombesin) and radiolabeling of the conjugates will be investigated with different radiometals (e.g., 89Zr, 68Ga). Radiolabeling kinetics and stability of the radioactive conjugates will be studied. The radioconjugates will be tested in vitro and in vivo to evaluate their biological properties (e.g., tumour targeting capabilities and pharmacokinetics). Expected value of the proposed projects: The proposed research will provide an additional dynamic impulse towards the development of new and effective radiodiagnostics useful in nuclear medicine. Significant resonance from different research areas related to molecular imaging is expected, both from academia and the pharmaceutical industry.
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