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Rationale <p>Somatostatin receptor subtype 2 (SSTR2) is a G-protein coupled receptor overexpressed in multiple cancers, including neuroendocrine tumors, small cell lung cancer, and hepatocellular carcinoma<b>.</b> Clinical validation of SSTR2-targeted radioligand therapy (Lutathera™) has driven development of next-generation ligands. Progress in next-generation SSTR2 ligand development is strengthened by quantitative platforms that preserve native receptor context and enable quantitative, cross-species binding data to drive translation and radiotherapeutic advancement.</p> Methods <p>Fresh-frozen tissue sections from mouse, rat, cynomolgus monkey and human brain were assessed for SSTR2 binding using the high affinity antagonist [<sup>177</sup>Lu]Lu-DOTA-LM3. Non-equilibrium kinetics and equilibrium binding methods were used to derive apparent affinity, target density, and affinity measurements. Section-wipe/gamma counting enabled absolute quantification without requiring isotope standards. Autoradiography and SSTR2 immunohistochemistry confirmed anatomic localization. Characterization of unlabeled DOTA-LM3 and its unlabeled lutetium- and gallium-complexed derivatives were compared to assess the effects of radiometal conjugation.</p> Results <p>Across all species, [<sup>1</sup>⁷⁷Lu]Lu-DOTA-LM3 exhibited specific, saturable binding characteristic of a single class of high-affinity sites. Autoradiography signals co-localized with SSTR2-rich regions identified by immunohistochemistry, confirming expected distribution patterns. Affinities derived from unlabeled and radiolabeled DOTA-LM3 were consistent, validating assay reproducibility. Whilst affinities of agonists and antagonists were conserved across species, radiometal substitution altered ligand properties: the lutetium-complexed form preserved affinity comparable to the chelator-only ligand, while the gallium-complexed variant showed markedly reduced affinity.</p> Conclusions <p>This native-tissue platform provides efficient, translatable, reproducible and absolute quantification of SSTR2 ligand binding without tissue standards, supporting early selection of chemotypes, radiometals, and species-bridging expectations before <i>in vivo</i> studies.</p>

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Cross-Species Quantitative Benchmarking of SSTR2 Radioligands in Fresh-Frozen Brain Sections: An Adaptable Framework for Radiopharmaceutical Development

  • 期刊论文

  • 发表日期：

    2026年7月9日

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  • Caitlin McCutcheon,
  • Zachary Lawrence,
  • Marie James,
  • Taryn Palluccio,
  • Maha Chowdhury,
  • Pradeep K. Singh,
  • Kelly Orcutt,
  • Shil Patel

摘要

Rationale

Somatostatin receptor subtype 2 (SSTR2) is a G-protein coupled receptor overexpressed in multiple cancers, including neuroendocrine tumors, small cell lung cancer, and hepatocellular carcinoma. Clinical validation of SSTR2-targeted radioligand therapy (Lutathera™) has driven development of next-generation ligands. Progress in next-generation SSTR2 ligand development is strengthened by quantitative platforms that preserve native receptor context and enable quantitative, cross-species binding data to drive translation and radiotherapeutic advancement.

Methods

Fresh-frozen tissue sections from mouse, rat, cynomolgus monkey and human brain were assessed for SSTR2 binding using the high affinity antagonist [177Lu]Lu-DOTA-LM3. Non-equilibrium kinetics and equilibrium binding methods were used to derive apparent affinity, target density, and affinity measurements. Section-wipe/gamma counting enabled absolute quantification without requiring isotope standards. Autoradiography and SSTR2 immunohistochemistry confirmed anatomic localization. Characterization of unlabeled DOTA-LM3 and its unlabeled lutetium- and gallium-complexed derivatives were compared to assess the effects of radiometal conjugation.

Results

Across all species, [1⁷⁷Lu]Lu-DOTA-LM3 exhibited specific, saturable binding characteristic of a single class of high-affinity sites. Autoradiography signals co-localized with SSTR2-rich regions identified by immunohistochemistry, confirming expected distribution patterns. Affinities derived from unlabeled and radiolabeled DOTA-LM3 were consistent, validating assay reproducibility. Whilst affinities of agonists and antagonists were conserved across species, radiometal substitution altered ligand properties: the lutetium-complexed form preserved affinity comparable to the chelator-only ligand, while the gallium-complexed variant showed markedly reduced affinity.

Conclusions

This native-tissue platform provides efficient, translatable, reproducible and absolute quantification of SSTR2 ligand binding without tissue standards, supporting early selection of chemotypes, radiometals, and species-bridging expectations before in vivo studies.