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Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide
Xuejuan Wang1, Melpomeni Fani, Stefan Schulz
1Division of Radiological Chemistry, University Hospital Basel, Switzerland.
Purpose:
Targeting of tumours positive for somatostatin receptors (sst) with radiolabelled peptides is of interest for tumour localization, staging, therapy follow-up and targeted radionuclide therapy. The peptides used clinically are exclusively agonists, but recently we have shown that the radiolabelled somatostatin-based antagonist (111)In-DOTA-sst2-ANT may be preferable to agonists. However, a comprehensive study of this radiolabelled antagonist to determine its significance was lacking. The present report describes the evaluation of this novel antagonist labelled with (111)In and (177)Lu in three different tumour models.
Methods:
Radiopeptide binding, internalization and dissociation studies were performed using cells expressing HEK293-rsst(2). Biodistribution studies were performed in HEK293-rsst(2), HEK293-hsst(2) and HEK293-rsst(3) xenografted mice.
Results:
Saturation binding analysis confirmed earlier IC(50) data for (111/nat)In-DOTA-sst2-ANT and showed similar affinity of (177/nat)Lu-DOTA-sst2-ANT for the sst(2). Only low internalization was found in cell culture (6.68 ± 0.06 % at 4 h), which was not unexpected for an antagonist, and this could be further reduced by the addition of sucrose. No internalization was observed in HEK293 cells not expressing sst. Both results indicate that the internalization was specific. (111)In-DOTA-sst2-ANT and (177)Lu-DOTA-sst2-ANT were shown to target tumour xenografts expressing the rat and the human sst(2) receptor with no differences in their uptake or pharmacokinetics. The uptake in rsst(2) and hsst(2) was high (about 30 %IA/g 4 h after injection) and surprisingly long-lasting (about 20-23 %IA/g 24 h after injection). Kidney uptake was blocked by approximately 50 % by lysine or Gelofusine.
Conclusion:
These results indicate that radiolabelled somatostatin-based antagonists may be superior to corresponding agonists. The long tumour retention time of (177)Lu-DOTA-sst2-ANT indicates that this new class of compounds is of relevance not only in diagnostic imaging but also in targeted radionuclide therapy of sst-positive tumours.
Insights
Radiolabelled somatostatin antagonists show promise for targeting somatostatin receptor-positive tumors. The novel (177)Lu-DOTA-sst2-ANT exhibits long tumor retention, suggesting its utility in both imaging and radionuclide therapy.
Area of Science:
- Nuclear medicine
- Radiopharmaceutical chemistry
- Oncology
Background:
- Targeting tumors expressing somatostatin receptors (sst) with radiolabeled peptides is crucial for diagnostics and therapy.
- While clinical peptides are agonists, somatostatin-based antagonists like (111)In-DOTA-sst2-ANT may offer advantages.
Purpose of the Study:
- To comprehensively evaluate a novel somatostatin-based antagonist, (111)In-DOTA-sst2-ANT and (177)Lu-DOTA-sst2-ANT, in preclinical tumor models.
- To determine the significance of these radiolabeled antagonists compared to agonists.
Main Methods:
- In vitro: Radiopeptide binding, internalization, and dissociation studies using HEK293 cells expressing rat somatostatin receptor 2 (rsst(2)).
- In vivo: Biodistribution studies in mice bearing xenografts of HEK293-rsst(2), HEK293-hsst(2), and HEK293-rsst(3).
Main Results:
- The antagonist demonstrated specific binding and low internalization in cell cultures, characteristic of antagonist behavior.
- (111)In-DOTA-sst2-ANT and (177)Lu-DOTA-sst2-ANT effectively targeted tumors expressing both rat and human sst(2) receptors.
- High and sustained tumor uptake (approx. 30% IA/g at 4h, 20-23% IA/g at 24h) was observed, with kidney uptake reduced by lysine or Gelofusine.
Conclusions:
- Radiolabeled somatostatin antagonists may be superior to agonists for sst-positive tumor targeting.
- The prolonged tumor retention of (177)Lu-DOTA-sst2-ANT highlights its potential for both diagnostic imaging and targeted radionuclide therapy.
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