NECT-224 PET radiotracer targets Nectin-4 in bladder cancer

Many targeted cancer medicines only work if the relevant target structure is present on tumor cells. In urothelial carcinoma, the cell surface protein Nectin-4 can act as a binding site for antibody-coupled agents designed to eliminate tumor cells. However, Nectin-4 expression can vary between tumors, and metastases may even lose the protein, potentially reducing treatment effectiveness. Until now, a non-invasive imaging method to assess Nectin-4 content and heterogeneity before therapy has been lacking.

To address this gap, HZDR researchers chemically modified the bicyclic peptide drug conjugate BT8009 so it could be used for diagnostic imaging. The concept relies on radiotracers, molecules labeled with a radionuclide that bind to specific structures in the body and can be tracked using positron emission tomography (PET). This enables clinicians and clinical teams to see whether and where the compound binds to its target structure.

The team selected a bicyclic peptide as the carrier molecule because this class can offer stability and targeting performance in the body. Chemical adjustments, including replacing an oxidation-sensitive amino acid, enabled labeling with:

• Gallium-68 (Ga-68): supports fast, same-day nuclear medicine PET scans
• Copper-64 (Cu-64): longer half-life, potentially allowing higher-contrast images later

After in-depth testing in cell cultures and preclinical tumor models, NECT-224 labeled with Ga-68 or Cu-64 showed high binding specificity, clear tumor localization, and rapid clearance from surrounding tissue, key requirements for accurate PET imaging. These findings supported the first clinical application: in summer 2025, the Ga-68 version was used for the first time in a patient at Carl Gustav Carus University Hospital Dresden, where PET images clearly visualized the tumor.

“Using NECT-224 we can reveal whether a tumor really does carry Nectin-4 so that we can judge whether the patient affected will respond to targeted therapies,” explains Dr. Robert Wodtke, research associate at HZDR’s Institute of Radiopharmaceutical Cancer Research. “For us, the first successful use in humans was an important milestone and a strong signal that this tracer can offer genuine clinical added value.”

Alongside clinical testing, the team is working to extend residence time in tumor tissue and evaluate suitability for theranostic approaches that link diagnosis and therapy more closely. In the longer term, this could support therapy selection and contribute to “targeted radioligand therapies” (TRTs).

MEDICA-tradefair.com; Source: HZDR