Tracer Development Center - Bergen - 180°N
Tracer Development Center
The key and often limiting factor in nuclear medicine, and PET in particular, is the availability of radiopharmaceuticals, often referred to as “tracers”. Only a few of a large number of synthesized PET tracers reach the clinic or become clinically relevant despite their potential.
The primary objective of this proposal is to increase the number of clinically relevant radiotracers and make these available through strengthening the overall radiochemistry competence within 180°N. This objective will be met by establishing a consortium-wide tracer implementation framework based on the experience already gained in Bergen. Tracers primarily needed for the clinical multi-center studies will be made locally available throughout the consortium. Novel tracers will be multi-center validated, drawing on the combined expertise, competence and resources.
In order to address these issues, we aim to streamline the whole radiotracer production and validation process at all involved sites. The consortium members will jointly validate and prepare manufacturing authorizations to the Norwegian Medicinal Agency (NOMA). This will not only speed up the process, but also make more PET-tracers locally available across all PET centers in Norway and concomitantly speed up the process. The long-term goals are to provide better health care, improve the decision-making process and reduce the currently very high costs for shipment of tracers. This will also exploit the potential in PET/MR multimodal imaging now available across the consortium. The increase in the number of available radiopharmaceuticals is by far due to efforts in radiochemistry, radiopharmaceutical and organic chemistry. 180 °N will comprise a cross-disciplinary team with a long and well-established experience in organic synthesis, organometallic and pharmaceutical chemistry. Together the joint effort will be made to develop new PET tracers and theranostic approaches. The Bergen research package will work synergistically with those headed by Tromsø and Trondheim in 180°N.
Work Packages:
In WP1 “Precursor and Radiolabeling Methodology” we will use contemporary organic synthesis strategies for preparing facile radiolabeling substituents. This will include catalytic functionalization for 18F or 11C labeling, solid supported resin-bound methods and other late stage functionalization strategies. The strategies explored here will also be developed into methods for instrumental radiolabeling using current radiosynthesis modules and tools for routine high-activity production runs. Novel strategies for late-stage functionalization will be explored with the aim of synthesizing novel precursor molecules for fast and efficient radiolabeling. Novel radiolabeling methods based on the use of transition metals as the radionuclide will be pursued both for novel precursors as well as in comparison with established tracers. Regulatory aspects will also have to be considered here as methods should comply with e.g. European Pharmacopoeia requirements. This is important in order to make methods robust and increase availability.
The work proposed under this WP will be conducted in close collaboration with WP3.
Principal Investigators:
- Hans-René Bjørsvik, Professor, UiB
- Jørn H. Hansen, Associate Professor, Chemical Synthesis and Analysis, UiT
Radiolabeling with the promising radionuclide 45Ti and their immobilization on relevant peptides and development of peptide-chelator conjugates for immuno-PET imaging applications will be in focus.
We are aiming to implement an efficient method for 45Ti isotope trapping via diol- functionalized resins, subsequently study the decomplexation of resin-bound 45Ti by wrapping the titanium with multidentate and hydrophilic chelators that can either directly or in a separate step be conjugated to pre-functionalized peptides. The development a method that allows for this to take place in aqueous solution will be a major focus of WP2.
A large part of the work will be dedicated to shortening and simplify the preparation procedures and at the same time increasing the hydrolytic stability of titanium compounds. In order to further extend the synthetic methodology based on 45Ti complexes as radiotracers, peptides bearing specific epitopes for binding to tumor-cell specific proteins will be targeted as radiometal carriers for expanding its applicability toward imaging applications. For this purpose, post-functionalization of water-soluble peptides allowing the transfer in aqueous phase of the capped 45Ti complexes with multidentate hydrophilic chelators will be investigated, with a particular focus on their kinetic inertness under in vivo conditions.
To support the pre-clinical activities, lead by Tromsø, peptide candidates with appropriate metal chelator functionality for 64Cu, 89Zr, 177Lu and 225Ac will be prepared by our experts.
Principal Investigators:
- Bengt Erik Haug, Professor, UiB
- Erwant Le Roux, Associate Professor, UiB
This work package will draw the current consortium wide expertise in kinase inhibitors (KIs) and jointly develop small molecule KIs for imaging and treatment of brain tumors. To achieve our goals we will utilize a dual strategy: Development of novel KIs radiolabeled with 11C and 18F and development of novel bioconjugates containing a therapeutic radiometal.
Despite the challenges of crossing the blood brain barrier (BBB) and high levels of efflux transporters present, KIs for management of brain tumors is a desirable treatment strategy. We propose to approach this by using PET nuclide labeled KIs, relevant pre-clinical models and modeling methods to better understand the mechanisms behind the disease and thus better rational design of appropriate tracers. Due to the BBB challenges, the secondary goal here will be improving KIs in targeting cancer in general.
Microglia are the primary immune cells of the central nervous system comprised of mononuclear phagocytes, belonging to the glial system of non-neuronal cells that support and protect neuronal functions. The main functions of the microglia are neuroprotection and immune defense. Microglial cells seem to stem from primitive myeloid progenitors.
The CSF1R is a key regulator of myeloid lineage cells and genetic loss of CSF1R has shown reduction and elimination of 99% of the microglial cells in the total brain volume. By targeting the microglia cells and the CSF1R the potential of producing a powerful radiotracer for neuroinflammation, brain injuries, Parkinsons disease, cancer such as gliomas and Alzheimer disease is served.
Principal Investigator:
- Eirik Sundby, Associate Professor, NTNU
Development of new tracers takes on average 13 years, similar to other pharmaceuticals. In order to increase patient care and precision diagnostics during the timeframe of this project, much attention will be given to WP4 “Tracer Implementation” to increase the number of locally available PET tracers.
Due to the aforementioned costs associated with transport and logistics, the primary goal for WP4 is therefore to implement and get approval for relevant tracers for all consortium partners as soon as possible. The increased regulatory requirements will necessitate a joint effort in providing PET tracers to the clinic. This work will build on a decade of experience and expertise from similar work from the Bergen group at Haukeland University Hospital.
The key to this process is to establish a consortium wide working group that jointly will perform necessary qualifications and validations for successful manufacturing authorization required under Norwegian and European law. The work conducted and experience gained will be fundamental in order to conduct clinical trials with drug candidates developed within the consortium.
Principal Investigators:
- Ole Heine Kvernenes, Chemist, Haukeland University Hospital
- Rune Gildsig, Haukeland University Hospital