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.
Work package 1:
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…
Work package 2:
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…
Work package 3:
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….
Work package 4:
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…