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Purpose <p><sup>68</sup>Ga- and <sup>177</sup>Lu-labeled theranostic companion tracers have become a mainstay in the clinical management of SST<sub>2</sub> overexpressing neuroendocrine tumors. Despite the excellent radionuclide characteristics of [<sup>18</sup>F]fluorine for PET imaging, <sup>18</sup>F-labeled SST<sub>2</sub>-targeted tracers remain underrepresented. Novel radiohybrid SST<sub>2</sub>-tracers with DOTA as a bridging unit were designed, allowing radiolabeling with either <sup>18</sup>F or <sup>68</sup>Ga.</p> Methods <p>Seven DOTA-TATE derivatives (rhTATE1/2: <i>N</i>-SiFA<i>lin</i>-<i>N</i>,<i> N</i>-Me<sub>2</sub>-Gly-<span>d</span>-Dap/Lys(<i>trans</i>-DOTA-TATE)-OH and (rhTATE2.1-2.5: H-AA1-AA2-AA3-<span>d</span>-Dap(<i>N</i>-SiFA<i>lin</i>-<i>N</i>,<i> N</i>-Me<sub>2</sub>-Gly)-<span>d</span>-Lys(<i>trans</i>-DOTA-TATE)-OH) with different linkers and hydrophilic modifiers (AA1-AA3) were synthesized and compared to [<sup>18</sup>F]SiTATE. Competitive binding studies (IC<sub>50</sub>) were performed using hSST<sub>2</sub>-CHO cells and [<sup>125</sup>I]TOC. Internalization was investigated using AR42J cells. Biodistribution and PET/CT studies were performed using AR42J xenograft bearing CD1 nu/nu mice. SST<sub>2</sub> specificity was confirmed in a blocking study (+/- co-injection of octreotide).</p> Results <p>While the first-generation compounds showed good affinity (IC<sub>50</sub>: [<sup>nat</sup>Ga]rhTATE1: 5.6 ± 1.4 n<span>m</span>, [<sup>nat</sup>Ga]rhTATE2: 5.7 ± 0.2 n<span>m</span>) but high lipophilicity (LogD<sub>pH=7.4</sub> = -1.03 and − 1.19), the inclusion of hydrophilic modifiers ([<sup>nat</sup>Ga]rhTATE2.1-[<sup>nat</sup>Ga]rhTATE2.5) improved affinity (IC<sub>50</sub>: 2.6 to 3.7 n<span>m</span>) and hydrophilicity (LogD<sub>pH=7.4</sub> = -2.30 to -2.12). The compounds demonstrated efficient internalization (357% to 841% compared to [<sup>125</sup>I]TOC), and variable human serum albumin affinity (84.8% to 98.8%). [<sup>18</sup>F][<sup>nat</sup>Ga]rhTATE2.2 showed the highest tumor accumulation (27.9 ± 4.8%iD/g), while [<sup>18</sup>F][<sup>nat</sup>Ga]rhTATE2.5 showed lower tumor uptake (18.6 ± 6.2%iD/g), but substantially lower background accumulation, providing improved tumor-to-organ ratios.</p> Conclusion <p>This study demonstrates a SST<sub>2</sub>-targeted radiohybrid concept using bifunctionalized DOTA as a bridging unit. <i>N</i>-terminal modifications with hydrophilic tripeptides improved the pharmacokinetic properties. [<sup>18</sup>F][<sup>nat</sup>Ga]rhTATE2.5 (<span>d</span>-Glu-<span>d</span>-Glu-<span>d</span>-Glu) compares particularly well to [<sup>18</sup>F]SiTATE regarding background clearance and tumor accumulation, with the additional advantage of radiohybrid radiolabeling.</p>

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Novel radiohybrid PET-Tracers for SST2-targeted imaging of neuroendocrine tumors

  • 期刊论文

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  • 发表日期：

    2025年10月23日

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  • Lennard Wendlinger,
  • Mara Parzinger,
  • Alexandra Litvinenko,
  • David Viertl,
  • Philipp Spatz,
  • Alexander Wurzer,
  • Hans-Jürgen Wester,
  • Margret Schottelius

摘要

Purpose

68Ga- and 177Lu-labeled theranostic companion tracers have become a mainstay in the clinical management of SST2 overexpressing neuroendocrine tumors. Despite the excellent radionuclide characteristics of [18F]fluorine for PET imaging, 18F-labeled SST2-targeted tracers remain underrepresented. Novel radiohybrid SST2-tracers with DOTA as a bridging unit were designed, allowing radiolabeling with either 18F or 68Ga.

Methods

Seven DOTA-TATE derivatives (rhTATE1/2: N-SiFAlin-N, N-Me2-Gly-d-Dap/Lys(trans-DOTA-TATE)-OH and (rhTATE2.1-2.5: H-AA1-AA2-AA3-d-Dap(N-SiFAlin-N, N-Me2-Gly)-d-Lys(trans-DOTA-TATE)-OH) with different linkers and hydrophilic modifiers (AA1-AA3) were synthesized and compared to [18F]SiTATE. Competitive binding studies (IC50) were performed using hSST2-CHO cells and [125I]TOC. Internalization was investigated using AR42J cells. Biodistribution and PET/CT studies were performed using AR42J xenograft bearing CD1 nu/nu mice. SST2 specificity was confirmed in a blocking study (+/- co-injection of octreotide).

Results

While the first-generation compounds showed good affinity (IC50: [natGa]rhTATE1: 5.6 ± 1.4 nm, [natGa]rhTATE2: 5.7 ± 0.2 nm) but high lipophilicity (LogDpH=7.4 = -1.03 and − 1.19), the inclusion of hydrophilic modifiers ([natGa]rhTATE2.1-[natGa]rhTATE2.5) improved affinity (IC50: 2.6 to 3.7 nm) and hydrophilicity (LogDpH=7.4 = -2.30 to -2.12). The compounds demonstrated efficient internalization (357% to 841% compared to [125I]TOC), and variable human serum albumin affinity (84.8% to 98.8%). [18F][natGa]rhTATE2.2 showed the highest tumor accumulation (27.9 ± 4.8%iD/g), while [18F][natGa]rhTATE2.5 showed lower tumor uptake (18.6 ± 6.2%iD/g), but substantially lower background accumulation, providing improved tumor-to-organ ratios.

Conclusion

This study demonstrates a SST2-targeted radiohybrid concept using bifunctionalized DOTA as a bridging unit. N-terminal modifications with hydrophilic tripeptides improved the pharmacokinetic properties. [18F][natGa]rhTATE2.5 (d-Glu-d-Glu-d-Glu) compares particularly well to [18F]SiTATE regarding background clearance and tumor accumulation, with the additional advantage of radiohybrid radiolabeling.