Development of efficiently conjugatable hybrid bimodal synthons with radionuclide and fluorescent dye applicable in combined PET/OI

• Applicant: Professorin Dr. Carmen Wängler
• Subject Area: Pharmacy ; Medical Physics, Biomedical Technology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 326183283

The imaging modalities Positron Emission Tomography (PET) and Optical Fluorescence Imaging (OI) are currently not used in combination for tumor imaging applications, although a combined approach could offer important advantages: PET enables the highly sensitive visualization of tumorous tissues throughout the body whereas optical fluorescence imaging during a following curative surgical intervention allows for the reliable identification of tumor boundaries, enclosed small metastases and also transformed malignant lymph nodes and thus has the potential to increase the therapeutic efficiency.For such a combined imaging approach, hybrid markers have to be developed which allow for a visualization by both imaging modalities.So far, there are no hybrid bimodal synthons available which enable the efficient introduction of both markers (radionuclide and fluorescent dye) in a single position of a tumor-affine ligand and furthermore exhibit a sufficiently high stability combined with an only minor alteration of the biodistribution of the conjugated tumor-affine ligand. Thus, the aim of this project is to develop such hybrid bimodal synthons.For this development, different fluorophores (emitting light extending from the visible to the near-infrared spectrum) and a chelator (which can be labeled with 68Ga und 64Cu) are to be combined and the obtained synthons are to be functionalized so that their efficient and chemoselective conjugation to biomolecules becomes feasible. The chemical syntheses of these hybrid synthons are to be followed by their radiolabeling and demonstration of sufficient stability. Furthermore, the hybrid synthons will be chemically optimized regarding hydrophilicity to minimize the influence of the introduced hybrid synthons into tumor-affine ligands on the biodistribution of the obtained conjugates.As proof-of-concept, different of the developed hybrid synthons are to be conjugated to a tumor-affine model substance (GRPR-binding peptide dimer) and the radiolabeling and binding affinity of the conjugates to their target receptor are to be evaluated in vitro. The obtained, dually labelled tumor-affine ligands are finally to be evaluated regarding their pharmacokinetics and tumor accumulation in vivo in tumor-bearing mice via small animal PET/CT and small animal fluorescence imaging to show the applicability of the hybrid synthons in biomolecule derivatization and subsequent diagnostic tumor PET and fluorescence imaging.

• DFG Programme: Research Grants