Novel radiohybrid-based CCK-2R-targeted Ligands for Imaging and Targeted Radiotherapy of Medullary Thyroid Cancer

• Applicants: Dr. Veronika Felber, since 5/2023; Professor Dr. Constantin Lapa
• Subject Area: Radiology ; Pharmacy
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 461577150

Aim of this project is the development of radiohybrid (rh) peptide radiopharmaceuticals that target the cholecystokinin-2 receptor (CCK-2R) overexpressed in approximately 90% of all MTCs. Based on the experience gained with our recently developed rh-based PSMA tracers, we will use isotopic exchange (IE) in combination with chelator chemistry to allow 18F-labeling and radiometallation with PET and therapeutic isotopes. All tracers will be extensively evaluated in vitro and in vivo by means of established state-of-the-art methods. After successful tracer development and pre-clinical assessment of the novel rh-based CCK-2R-targeted ligands, we intend to initiate a Phase 1 Clinical Trial at the University Hospital of Augsburg by means of separate funding at the end of this (pre-clinical) project. Given the importance of early detection of disease recurrence in localized stages in order to allow for curative (re-)treatment and the urgent need for an optimized PET agent, CCK-2R-targeted ligands could successfully address an unmet clinical need. To date, PET/CT imaging with either tracer is not recommended until basal calcitonin levels reach 150 pg/nL. As a potential clinical application, patients seen at the thyroid outpatient clinic of the Uni-versity Hospital of Augsburg with biochemical MTC recurrence (with calcitonin levels > 150 pg/nL) and inconclusive anatomical imaging as well as [18F]DOPA PET/CT work-up might be asked to undergo additional CCK-2R-tageted PET/CT in order to detect MTC le-sions and guide further treatment. In case of an improved diagnostic outcome, clinical translation would thus occur rapidly. In a next step, additional whole body dosimetry with 177Lu-labeled CCK-2R-targeted compounds could be performed in selected patients (failure or intolera-bility of TKI treatment) with systemic progressive disease and intense receptor expression of all tumor lesions in order to assess the possibility of CCK-2R-targeted radiotherapy.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Thomas Günther, until 4/2023