In vivo imaging of tropomyosin receptor kinase (Trk) status in cancer for therapeutic outcome prediction with Positron Emission Tomography (PET) and investigation of Trk status linked to neurodegenerative disease progression
Organic Molecular Chemistry - Synthesis and Characterisation
Final Report Abstract
Nowadays an early stage detection and evaluation of brain-cancer or disorder, e.g. Alzheimer and Pakinson diseases, is hardly feasible without surgery. In the last decade the Schirrmacher group has been focused on the syntheses and development of highly selective Tropomyosin receptor kinase (TrkA, B, C) inhibitor radiotracers for the positron emission tomography (PET). This approach represents a non-invasive method to detect dysfunctions in brain whereas Trks are critically involved in the development of the nervous system and a dysregulation of Trk signaling is recognized as a hallmark of neurodegenerative diseases. The most promising scaffold the Schirrmachers group investigated based on 2-phenylpyrrolidines fragments of imidazo[1,2-b]pyridazines. The main part of the project was to synthesize modification eligible molecules for tracking Trk status regarding to a sufficient increase in brain uptake through increasing the pKa value by introducing one or two fluorides at the pyrrolidine part. Furthermore, a conformational lock by macrocyclization was targeted. The monofluorinated standard and precursor derivate was fully synthesized. Furthermore, the difluorinated compound were synthesized up to step six of eight. In the case of the macrocyclic compound the yields of originally planned synthetic route were inadequate because of obtaining intermolecular reactions. Two alternate routes were advised and will be under further investigation. Besides the main project silicium fluoride acceptor (SiFA) modified β-cyclodextrine(CD)-peptide conjugates were synthesized. Unfortunately a fully separation of the product and the startmaterial was not achieved. Moreover, in collaboration with Dr. J. J. Bailey, the evaluation and optimization of novel 18F-labeling techniques for SiFA compounds were studied by varying the pHe value and the base-toprecursor-ratio. Here we showed that a pHe of 8-9 and a ratio of >0.02 led to the most promising results. Further investigations will be focused on the labeling of highly complex and base labile compounds.
Publications
- (2018), 18F-Radiolabeling and In Vivo Analysis of SiFA-derivatized Polymeric Core-Shell Nanoparticle. Bioconjugate Chem., 29, 89-95
S. Berke, A.-L. Kampmann, M. Wuest, J. J. Bailey, B. Glowacki, F. Wuest, K. Jurkschat, R. Weberskirch, R. Schirrmacher
(See online at https://doi.org/10.1021/acs.bioconjchem.7b00630)
