Illustration of how NECT-224 works: Bicyclic peptides labeled with radioactive markers (light blue chains) flow through blood vessels toward tumor cells and bind specifically to the surface protein Nectin-4 (orange arc). Credit: HZDR/A.Gruetzner

A research team at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) has developed a radiopharmaceutical molecule marker that can visualize tumors that carry the cell surface protein Nectin-4. This primarily occurs in the body in cases of urothelial carcinoma, a common form of bladder cancer.

In pre-clinical trials, the drug candidate, NECT-224, proved stable and was successfully used in humans for the first time. As the team has now reported in the Journal of Medicinal Chemistry, in the future, it could be used to better identify patients who would benefit from Nectin-4-targeted therapies.

Many modern cancer drugs only work when the target structure to which they are supposed to bind is also present on the tumor cells. In the case of urothelial carcinoma, the cell surface protein Nectin-4 lends itself to this purpose. It serves as a "door sign" for antibody-coupled agents that are able to eliminate tumor cells in a targeted fashion. But not every tumor produces the same amount of Nectin-4.

Metastases, that is, secondary tumors that spread from the primary tumor, can even lose the protein, resulting in the therapies being less effective. Up to now, there has been no noninvasive method for reliably determining the content and heterogeneity of Nectin-4 by imaging prior to therapy—an obstacle to making precise treatment decisions.

In order to solve this problem, HZDR researchers chemically modified the bicyclic peptide drug conjugate BT8009 to make it suitable for diagnostic imaging. Their approach is based on radiotracers: molecules labeled with a radionuclide which bind specifically to certain structures in the body and whose distribution can be determined with the help of imaging techniques like positron emission tomography (PET). This allows researchers to trace whether and where the active agent in the body binds to its target structure noninvasively.

The researchers chose a so-called bicyclic peptide as their carrier molecule. This class of molecules is characterized by high targeting accuracy and good stability in the body. By chemical modification—including replacing an oxidation-sensitive amino acid—a series of robust peptide variants was produced that can be labeled with radioactive isotopes like Gallium-68 and Copper-64.

Nectin-4 can be revealed in both variants using PET, but they differ in their diagnostic application: Gallium-68 enables fast, same-day nuclear medical PET examinations while, due to its longer half-life, Copper-64 allows potentially higher-contrast images to be achieved at a later date.

First application at Dresden University Hospital

The new tracers initially underwent in-depth testing in cell cultures and, subsequently, in pre-clinical tumor models. Labeled with Gallium-68 or Copper-64, NECT-224, in particular, revealed high binding specificity, clear tumor localization, and rapid clearance from the surrounding tissue—important preconditions for precise PET imaging. These convincing results paved the way for the first clinical application. In summer 2025 at Carl Gustav Carus University Hospital Dresden, the Gallium-68 variant of NECT-224 was used on a patient for the first time. The PET images clearly presented the tumor and thus confirmed the pre-clinical results on the suitability of NECT-224.

"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 trials, the research team is working on further optimizing NECT-224. Their aim is to extend the residence time in the tumor tissue and to test the tracer’s suitability for future theranostic approaches—that is, concepts that interlink diagnosis and therapy even more closely. In the long term, this would not only mean the marker could help to select appropriate therapies but also serve as a basis for new treatment strategies, known as "targeted radioligand therapies" (TRTs).

More information

Tobias Krönke et al, "Precision on Two Wheels"─Structural Refinement of64Cu- and68Ga-Labeled Bicyclic Peptides Targeting Nectin-4 for Improved Tumor Imaging: From Preclinical Development to First-in-Human Application, Journal of Medicinal Chemistry (2025). DOI: 10.1021/acs.jmedchem.5c02371

Journal information: Journal of Medicinal Chemistry

Citation: Radiotracers could improve choice of bladder cancer therapies (2026, January 8) retrieved 8 January 2026 from https://medicalxpress.com/news/2026-01-radiotracers-choice-bladder-cancer-therapies.html

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