Amyloid deposition in pancreatic islets, formed from islet amyloid polypeptide (amylin), is a common pathologic feature of type 2 diabetes mellitus (T2DM) found in more than 90% of T2DM patients. The non-invasive, repeatable, in vivo imaging visualization of amylin aggregates would be an invaluable tool for early diagnosis of T2DM, but also for the evaluation of potential anti-amyloid therapies; however, today it represents an unmet need. We propose the design, synthesis, in vitro and in vivo validation of imaging probes based on metal complexes for the detection of amylin aggregates.
We will use a modular approach to create these probes where a targeting unit, capable of selective binding to the amylin aggregates is linked to a metal chelate which acts as an imaging reporter. The major advantage of this approach is that a large number of metal ions exist that can be used as imaging probes for a variety of imaging modalities. The most important are Gd3+ for MRI detection, and various radioactive isotopes for nuclear imaging. Several of these metal ions applicable as probes in the different imaging modalities have similar coordination chemistry characteristics and therefore can be easily substituted one by another in their complexes. Consequently, we can create a platform of imaging agents for various modalities by using the same chelator and targeting unit and choosing the appropriate metal ion for the imaging probe. In this project, the in vivo evaluation will be focused on MR imaging with the Gd3+ and SPECT imaging with the 111In3+ analogues, using appropriate mice models. Indeed, longitudinal and pathological studies of pancreas morphology are nearly impossible in humans, therefore we will mimic pancreatic amylin aggregates in mice models. It will allow us to run longitudinal studies with a significant number of animals per group.
This interdisciplinary project combines chemistry and biology and proposes an innovative imaging approach based on novel imaging agents with possible future human applications. First, the results will contribute to a better understanding of the interactions at the molecular level between metal-complexes as imaging probes and amyloid-type peptides. The in vivo data will validate the potential of these probes as imaging agents in T2DM. On a longer term, the results of this project can contribute to propose a solution to an identified but unmet medical need, as so far no specific MRI agents have been reported for amylin visualization in T2DM.
Madame Eva JAKAB TOTH (Centre de Biophysique Moléculaire)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CBM Centre de Biophysique Moléculaire
CNRS - LCC Centre National de la Recherche Scientifique - Laboratoire de Chimie de Coordination
INSERM-I2MC-UMR1048 Institut National de la Santé et de la recherche Médicale
Help of the ANR 524,317 euros
Beginning and duration of the scientific project: September 2016 - 48 Months