[^99mTc]Tc-PentixaTec: development, extensive pre-clinical evaluation, and first human experience

Area of Science:

• Nuclear Medicine
• Radiochemistry
• Oncology

Background:

• CXCR4 expression is crucial in hematologic malignancies.
• Non-invasive imaging of CXCR4 is clinically valuable.
• Existing PET agents like [68Ga]Ga-PentixaFor are effective but costly.

Purpose of the Study:

• To develop and evaluate novel 99mTc-labeled cyclic pentapeptides for SPECT imaging of CXCR4.
• To optimize labeling strategies and linker structures for improved affinity and targeting.
• To assess the preclinical and early clinical performance of a lead candidate, [99mTc]Tc-PentixaTec.

Main Methods:

• Synthesis of six mas3-conjugated CPCR4 analogs with varying linkers.
• Radiolabeling with 99mTc using mas3, HYNIC, and N4 strategies.
• In vitro binding and internalization studies using cancer cell lines.
• In vivo biodistribution and SPECT/CT imaging in mice.
• Early human SPECT/planar imaging and dosimetry in patients with hematologic malignancies.

Main Results:

• N4-L6-CPCR4 demonstrated the highest affinity (0.6 ± 0.1 nM) and efficient internalization (97% at 2h).
• [99mTc]Tc-N4-L6-CPCR4 ([99mTc]Tc-PentixaTec) showed high tumor uptake (8.6 ± 1.3% iD/g at 1h p.i.).
• Human studies confirmed good tolerability, favorable biodistribution, dosimetry (2.1-3.4 mSv), and excellent tumor-to-background ratios.

Conclusions:

• [99mTc]Tc-PentixaTec is a highly promising CXCR4-targeted SPECT agent.
• Optimization of linker and labeling strategies yielded a superior radiotracer.
• The agent exhibits excellent preclinical and clinical characteristics for diagnosing and monitoring CXCR4-expressing malignancies.