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Background <p>The biodistributions of radiometalated peptides and small molecules are greatly influenced by the charge conferred by the metal-chelator complex. Careful fine-tuning of this charge thus represents an attractive method to optimise pharmacokinetic properties. For this to be an effective strategy, numerous suitable chelators must be available for a given radiometal; each possessing a different net charge. Herein we report the synthesis of 2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAMGA), a bifunctional chelator for the <sup>203/212</sup>Pb theranostic pair containing a single negative charge, previously unattainable with reported radiolead chelators. DOTAMGA was incorporated into a radiopharmaceutical targeting the melanocortin 1 receptor (MC1R), a receptor highly expressed by melanomas, and evaluated in vivo against the commonly used radiolead chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic amide (TCMC).</p> Results <p>DOTAMGA was synthesised and conjugated to the MC1R targeting peptide MC1RL for subsequent investigation alongside TCMC-MC1RL. DOTAMGA-MC1RL and TCMC-MC1RL exhibited comparable affinity for MC1R in a series of competition binding assays with MC1R expressing cells. DOTAMGA-MC1RL was effectively labelled with <sup>212</sup>Pb and <sup>203</sup>Pb under standard radiolabelling conditions, and UV–Vis experiments demonstrated more rapid Pb<sup>2+</sup> complexation than TCMC-MC1RL. Both <sup>212</sup>Pb-labelled compounds remained &gt; 90% intact after 24&#xa0;h incubation in human serum. In B16F0 melanoma bearing C57BL/6 mice, DOTAMGA-MC1RL exhibited reduced hepatic uptake compared to TCMC-MC1RL, though a reduction in tumour uptake and resulting tumour to organ uptake ratios were also observed.</p> Conclusions <p>DOTAMGA represents a promising tool to optimise the pharmacokinetic properties of <sup>203/212</sup>Pb radiopharmaceuticals, and is a useful addition to existing radiolead chelators on account of its unique charge.</p>

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Synthesis and in vivo evaluation of a bifunctional, glutamic acid derived chelator for the 203/212Pb theranostic pair

  • 期刊论文

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  • 发表日期：

    2026年7月4日

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  • Jarred Michael Scaffidi-Muta,
  • Kwong Ching Li,
  • Didier Boucher,
  • Thomas Kryza,
  • William Tieu,
  • Andrew David Abell

摘要

Background

The biodistributions of radiometalated peptides and small molecules are greatly influenced by the charge conferred by the metal-chelator complex. Careful fine-tuning of this charge thus represents an attractive method to optimise pharmacokinetic properties. For this to be an effective strategy, numerous suitable chelators must be available for a given radiometal; each possessing a different net charge. Herein we report the synthesis of 2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAMGA), a bifunctional chelator for the 203/212Pb theranostic pair containing a single negative charge, previously unattainable with reported radiolead chelators. DOTAMGA was incorporated into a radiopharmaceutical targeting the melanocortin 1 receptor (MC1R), a receptor highly expressed by melanomas, and evaluated in vivo against the commonly used radiolead chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic amide (TCMC).

Results

DOTAMGA was synthesised and conjugated to the MC1R targeting peptide MC1RL for subsequent investigation alongside TCMC-MC1RL. DOTAMGA-MC1RL and TCMC-MC1RL exhibited comparable affinity for MC1R in a series of competition binding assays with MC1R expressing cells. DOTAMGA-MC1RL was effectively labelled with 212Pb and 203Pb under standard radiolabelling conditions, and UV–Vis experiments demonstrated more rapid Pb2+ complexation than TCMC-MC1RL. Both 212Pb-labelled compounds remained > 90% intact after 24 h incubation in human serum. In B16F0 melanoma bearing C57BL/6 mice, DOTAMGA-MC1RL exhibited reduced hepatic uptake compared to TCMC-MC1RL, though a reduction in tumour uptake and resulting tumour to organ uptake ratios were also observed.

Conclusions

DOTAMGA represents a promising tool to optimise the pharmacokinetic properties of 203/212Pb radiopharmaceuticals, and is a useful addition to existing radiolead chelators on account of its unique charge.