Tracer development for pancreatic β-cell imagingThe β-cells, which can be found in small structures within the pancreas called the islets of Langerhans, are necessary in normal metabolic function of the body, but are also of importance in a variety of diseases, such as diabetes mellitus, insulinomas, and congenital and adult hyperinsulinemic hypoglycemia (CHI and AHH, respectively). The glucagon-like peptide-1 receptor (GLP-1R) is highly abundant on the β-cells, thus making it a good target for radiopharmacy. In our approach, we target the GLP-1R with tracers based on the peptide exendin-4, which can be radiolabeled for diagnostic imaging or for therapy. It is very similar in structure to the endogenous ligand of GLP-1R, GLP-1, but is much more stable in the body. Exendin-4 tracers are already in clinical use for the detection of insulinomas, however, further improvement is needed to address some of their shortcomings, such as the characteristically high accumulation in the kidneys, which on one hand could distort the image obtained during a diagnostic scan (depicted in Figure Insulinoma), and on the other hand may have a negative impact on the patient’s health.
We have made a number of these improvements, such as further stabilization of the structure for better clinical use, and addressing the kidney uptake through changing the pharmacokinetic properties of the peptide. Currently, we are investigating the interaction between GLP-1R and its different ligands. This research is performed under the collaborative project BetaCure funded by the European Commission under the 7th framework program. The following members of the Radiopharmacology group are involved in this project: Simon Käppeli, Alain Blanc.
Insulinoma in close proximity to the kindeys, imaged with 68Ga-DOTA-Exendin-4 (Antwi et al. Journal of Nuclear Medicine (2015). 56: p1075-1078)
Targeting structure proteins in extracellular matrix (ECM)The extracellular matrix is the structure in the tissue which keeps the cells in the tissue together. It consists of around 300 proteins like collagen, fibronectin or elastin. It became evident over the last year that the role of ECM in diseases was underestimated. It plays an important if not major role in different diseases like invasive cancers, muscle dystrophy, fibrotic diseases etc DOI: nrm3904. The ECM interacts in different ways with the cells. In diseases it changes it stiffness (concentration of ECM proteins), the steric structure as well as the chemical structure of the proteins. The aim is to target these changes with peptides to develop new possibilities for diagnostic and therapeutic intervention in early stage of the disease. Therefore we developed in cooperation with the group of Prof. Viola Vogel a radiolabeled peptide which binds specifically to relaxed fibronectin. Fibronectin is stretched in healthy tissue but if the concentration becomes higher during the development of diseases the fibronectin structure is more and more relaxed and can be targeted with peptides derived from bacterial adhesins. We radiolabeled the peptide FnBPA5 and could show that we find a specific binding in to ECM in a prostate cancer in s.c. mouse model DOI: s41467-017-01846-0. We received a 4 year SNF grant including 2 PhD students for the further evaluation of this approach.
Therapy of gastrin derivatives
Different research efforts were made to overcome the kidney uptake problem. These research efforts are summarized in a review from the Radiopharmacy group in Njimegen. The research were the focused and combined in a european COST action in which 12 compounds were compared. The best compounds will be more deeply evaluated and will be applied as a therapeutic radiopharmaceutical first in preclinicals and later on if good results can be shown in clinical settings.