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