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Updated: Oct 10, 2025
Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression
Published on: February 3, 2023
Preliminary Study of New Gallium-68 Radiolabeled Peptide Targeting NRP-1 to Detect Brain Metastases by Positron
Albert Moussaron1, Valérie Jouan-Hureaux2, Charlotte Collet3,4
1Université de Lorraine, CNRS, LRGP, F-54000 Nancy, France.
Abstract:
Due to their very poor prognosis and a fatal outcome, secondary brain tumors are one of the biggest challenges in oncology today. From the point of view of the early diagnosis of these brain micro- and macro-tumors, the sensitivity and specificity of the diagnostic tools constitute an obstacle. Molecular imaging, such as Positron Emission Tomography (PET), is a promising technique but remains limited in the search for cerebral localizations, given the commercially available radiotracers. Indeed, the [18F]FDG PET remains constrained by the physiological fixation of the cerebral cortex, which hinders the visualization of cerebral metastases. Tumor angiogenesis is recognized as a crucial phenomenon in the progression of malignant tumors and is correlated with overexpression of the neuropilin-1 (NRP-1) receptor. Here, we describe the synthesis and the photophysical properties of the new gallium-68 radiolabeled peptide to target NRP-1. The KDKPPR peptide was coupled with gallium-68 anchored into a bifunctional NODAGA chelating agent, as well as Cy5 for fluorescence detection. The Cy5 absorbance spectra did not change, whereas the molar extinction coefficient (ε) decreased drastically. An enhancement of the fluorescence quantum yield (φF) could be observed due to the better water solubility of Cy5. [68Ga]Ga-NODAGA-K(Cy5)DKPPR was radiosynthesized efficiently, presented hydrophilic properties (log D = -1.86), and had high in vitro stability (>120 min). The molecular affinity and the cytotoxicity of this new chelated radiotracer were evaluated in vitro on endothelial cells (HUVEC) and MDA-MB-231 cancer cells (hormone-independent and triple-negative line) and in vivo on a brain model of metastasis in a nude rat using the MDA-MB-231 cell line. No in vitro toxicity has been observed. The in vivo preliminary experiments showed promising results, with a high contrast between the healthy brain and metastatic foci for [68Ga]Ga-NODAGA-K(Cy5)DKPPR.
Insights
A new gallium-68 peptide targeting neuropilin-1 (NRP-1) shows promise for diagnosing secondary brain tumors. This molecular imaging agent offers improved contrast for detecting brain metastases, addressing limitations of current diagnostic tools.
Area of Science:
- Oncology
- Molecular Imaging
- Radiochemistry
Background:
- Secondary brain tumors present a significant challenge in oncology due to poor prognosis and diagnostic limitations.
- Current molecular imaging techniques like [18F]FDG PET are hindered by physiological uptake in the brain, limiting detection of cerebral metastases.
- Neuropilin-1 (NRP-1) receptor is overexpressed in tumors and is a potential target for improved cancer diagnostics.
Purpose of the Study:
- To synthesize and characterize a novel gallium-68 radiolabeled peptide targeting the NRP-1 receptor for enhanced brain tumor imaging.
- To evaluate the in vitro and in vivo properties of the new radiotracer for potential application in diagnosing secondary brain tumors.
Main Methods:
- Synthesis of a gallium-68 labeled peptide (KDKPPR) conjugated to a NODAGA chelator and Cy5 for fluorescence detection.
- Radiosynthesis of [68Ga]Ga-NODAGA-K(Cy5)DKPPR with assessment of radiochemical yield, hydrophilic properties, and in vitro stability.
- In vitro evaluation of molecular affinity and cytotoxicity on endothelial and cancer cells, and in vivo assessment in a rat brain metastasis model.
Main Results:
- Efficient radiosynthesis of [68Ga]Ga-NODAGA-K(Cy5)DKPPR with favorable hydrophilic properties (log D = -1.86) and high in vitro stability (>120 min).
- No observed in vitro toxicity.
- Promising in vivo results in a rat brain metastasis model, demonstrating high contrast between healthy brain tissue and metastatic foci.
Conclusions:
- The novel [68Ga]Ga-NODAGA-K(Cy5)DKPPR radiotracer targeting NRP-1 is successfully synthesized and exhibits suitable properties for molecular imaging.
- Preliminary in vivo studies suggest this agent can effectively visualize brain metastases with high contrast, potentially improving early diagnosis.
- This NRP-1 targeting radiotracer holds promise for advancing the diagnostic capabilities in oncology for secondary brain tumors.
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