Kit for PET Imaging Agent to Support Regenerative Medicine Development

­Summary: Monitoring the fate of cells given to patients during regenerative medicine and cell therapies is an important milestone in their approval process.  Development of a simplified, one-step kit for  positron emission tomography imaging using 89Zr-oxine by researchers atKing’s makes such tracking easier. 
A kit for in-hospital preparation of radiopharmaceutical compounds containing the imaging agent zirconium-89-oxine ([89Zr]Zr-oxine) for positron emission tomography  starting from commercially supplied [89Zr]Zr-oxalate.  The formulation allows rapid, stable, high-yield (≥85%) preparation of [89Zr]Zr-oxine in a single step. The PET radiotracer kit is compatible with Good Manufacturing Practice standards (GMP), and is the first kit readily available  for cell tracking in clinical trials.
Developments in immune- and cell-based therapies have created a need to track the migration of individual administered cell types in vivo. Drug regulators are requiring that trials of cell-based therapies should be accompanied by methods to determine the location and fate of administered cells. Nuclear medicine imaging, and specifically positron emission tomography (PET) is the technology of election for such an in-vivo tracking. Among all known PET radiotracers, Zirconium-89 (89Zr) is one of the few positron emitter compounds that could meet the need for cell tracking over long, biologically relevant periods (more than 7 days). However, the current synthesis of 89Zr-oxine is particularly cumbersome, as it involves the use of organic solvents, exposes operators to high radiation doses and is operator-dependent, leading to large variability and failed syntheses.
The proposed technology allows rapid (~15 mins), stable, high-yield (> 89%), single-step preparation of [89Zr]Zr-oxine from commercially available 89Zr.
The synthetised radiotracer can be used either for labelling white blood cells for infection imaging or for labelling chimeric antigen receptors of (CAR-T) cells and stem cells for the development of immune- and cell-based therapies.
A similar formulation can also be used for the preparation of radiopharmaceutical compounds, such as together with [64Cu]Cu-oxine and [68Ga]Ga-oxine.
The technology is protected by a pending PCT patent application and is available for licensing. GMP-grade kits are currently under production.
The Science

Figure:  Preparation and use of the kit formulation for [89Zr]Zr-oxine. In a first step, 8-hydroxyquinoline is dissolved in water, followed by addition of HEPES and polysorbate 80 and pH adjustment to 7.9–8.0 with concentrated NaOH. This solution can be divided into single-use aliquots, e.g. one patient dose, and radiolabelled with commercial zirconium-89, copper-64 or gallium-68 as and when required. Alternatively, a central radiopharmacy facility could provide the radiolabelled product to the site performing the cell radiolabelling. The formulated [89Zr]Zr-oxine can be used to radiolabel various cell types, such as granulocytes or T-cells, without any further steps, for PET imaging. In the figure, it is also shown that the same method can be used for the preparation of [64Cu]Cu-oxine and [68Ga]Ga-oxine.
Patent Status
WO2021259869A1: pending PCT application.
Further Information
Francis M et al. (2020), "A kit formulation for the preparation of [89Zr]Zr(oxinate)4 for PET cell tracking: White blood cell labelling and comparison with [111In]In(oxinate)3", Nuclear Medicine and Biology, vol 90–91, pp. 31-40, doi:10.1016/j.nucmedbio.2020.09.002.
Patent Information:
For Information, Contact:
Ana Carina Araujo
King's College London
Rafael Torres Martin De Rosales
Philip Blower
Francis Man