Preclinical Study of a Dual-Target Molecular Probe Labeled with ⁶⁸Ga Targeting SSTR2 and FAP.

Area of Science:

• Nuclear Medicine
• Radiopharmaceutical Chemistry
• Oncology Imaging

Background:

• ⁶⁸Ga-labeled somatostatin analogs (SSAs) are standard for neuroendocrine tumor (NET) diagnosis.
• Optimizing tumor uptake and retention is crucial for effective peptide receptor radionuclide therapy (PRRT).
• Current tracers may have limitations in maximizing target engagement for dual-receptor-expressing tumors.

Purpose of the Study:

• To design and synthesize a novel ⁶⁸Ga-labeled heterodimer tracer, ⁶⁸Ga-TATE-46.
• To evaluate if this heterodimer tracer offers improved pharmacokinetic properties and tumor targeting compared to monomeric tracers.
• To assess the potential of ⁶⁸Ga-TATE-46 for enhanced imaging of tumors expressing both somatostatin receptors (SSTR2) and fibroblast activation protein (FAP).

Main Methods:

• Synthesis of ⁶⁸Ga-TATE-46 using TATE and FAPI-46 precursors.
• Verification of labeling efficiency and stability using Radio-HPLC.
• In vitro and in vivo evaluation of receptor binding, tumor targeting, cell uptake, pharmacokinetics, Micro PET imaging, and biodistribution in NCI-H727 (SSTR2/FAP positive) and Mc38 (SSTR2/FAP negative) tumor models.
• Comparison with ⁶⁸Ga-DOTA-TATE and ⁶⁸Ga-FAPI-46.
• Confirmation of dual-receptor targeting via blocking studies and immunohistochemistry.

Main Results:

• ⁶⁸Ga-TATE-46 demonstrated comparable SSTR2 and FAP targeting to monomeric analogs.
• Significantly higher tumor uptake was observed for ⁶⁸Ga-TATE-46 in SSTR2/FAP positive tumors compared to both ⁶⁸Ga-DOTA-TATE and ⁶⁸Ga-FAPI-46 (p < 0.001).
• Blocking studies confirmed the dual-receptor targeting characteristics of ⁶⁸Ga-TATE-46 in vivo.

Conclusions:

• The dual-target tracer ⁶⁸Ga-TATE-46 exhibits improved tumor uptake, retention, and pharmacokinetics over mono-specific tracers.
• ⁶⁸Ga-TATE-46 is an effective probe for non-invasive detection of tumors co-expressing SSTR2 and FAP.
• Further investigation into the clinical application of ⁶⁸Ga-TATE-46 for SSTR2 and FAP-related tumors is warranted.