Development of radiolabeled heterobivalent GRPR- and NPY(Y1)R-bispecific peptidic ligands for a highly sensitive and specific visualization of human breast cancer with PET

• Applicant: Professorin Dr. Carmen Wängler
• Subject Area: Pharmacy ; Medical Physics, Biomedical Technology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 463348412

The functional and specific imaging of malignant diseases most commonly uses the addressing of receptors overexpressed on the tumor cell surface. To these, radiolabeled receptor-specific agents can bind, thus enabling the visualization of tumors e.g. by PET/CT imaging. However, it was shown for several human tumor entities that they exhibit a high inter- and intraindividual variability of the respective target receptor expression. The receptor expression profile can furthermore considerably change upon tumor de-differentiation, metastasis or tumor therapy, further limiting the achievable sensitivity of receptor-specific imaging.An example of a tumor entity that can overexpress several different receptor types in parallel or complementarily is human breast cancer, which can carry different receptor types in relevant amounts. It could be shown in systematic studies on human tumor biopsies that two receptor types, namely the GRPR (gastrin-releasing peptide receptor) and the NPY(Y1)R (neuropeptide Y receptor, subtype 1) are most frequently overexpressed but also achieve expression rates of only 74% and 66-85%, respectively. This makes clear that a visualization of human breast cancer cannot reach a high sensitivity using a monospecific radioligand for tumor targeting. However, given that 93% of lesions carry at least one of these two receptors in high density, the sensitivity of specific receptor-mediated imaging of human breast cancer using PET could be significantly increased using radiolabeled heterobivalent ligands being able to bind to both receptor types. The aim of this radiochemical basic research project is therefore the development of a GRPR- and NPY(Y1)R-bispecific heterobivalent peptide-based radioligand for specific and furthermore sensitive imaging of human breast cancer using PET.For the realization of the project, previous experiences of the working group in the development of such systems can be used as a basis for the development of new, structurally and pharmacokinetically optimized radioligands.Within the course of the project, the chemical synthesis of the complex target compounds and their radiolabeling with 68Ga and 64Cu will be established first. Besides the heterobivalent bispecific target radioligands, also heterobivalent monospecific and monovalent reference compounds will be synthesized.This is followed by the in silico determination of the hydrophilicity/lipophilicity and stability of the substances as well as the determination of their in vitro GRPR and NPY(Y1)R receptor binding affinities.Finally, the developed radioligands will be examined in a xenograft mouse model in comparison to the reference compounds in order to determine the potential of the newly developed compounds with respect to a clinical translation and their ability to improve the sensitivity of human breast cancer visualization.

• DFG Programme: Research Grants