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Published on: January 29, 2019
Double-stabilized neurotensin analogues as potential radiopharmaceuticals for NTR-positive tumors
Elisa García-Garayoa1, Veronique Maes, Peter Bläuenstein
1Center for Radiopharmaceutical Science, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland. elisa.garcia@psi.ch
Introduction:
Overexpression of neurotensin (NT) receptors in exocrine pancreatic cancer and other neuroendocrine cancers make them interesting targets for tumor imaging and therapy. Modifications at the cleavage bonds 8-9 and 11-12 led to the synthesis of NT-XII, NT-XIII and NT-XVIII, three new stabilized analogues. (NalphaHis)Ac was coupled to the N-terminus for labeling with [(99m)Tc]-tricarbonyl.
Methods:
Stability was tested in vitro in human plasma and HT-29 cells. Binding to NT1 receptors and internalization/efflux were analyzed in intact HT-29 cells. Biodistribution studies were performed in nude mice bearing HT-29 xenografts.
Results:
All analogues were very stable in human plasma, with half-lives of 20-21 days. Degradation in HT-29 cells was more rapid (t(1/2) of 6.5, 5 and 2.5 h for NT-XII, NT-XIII and NT-XVIII, respectively). They also showed high affinity and specificity for NT1 receptors. Bound activity was rapidly internalized at 37 degrees C. The pattern of externalization was different. NT-XII was released more slowly than NT-XIII and NT-XVIII (half of the activity still inside the cells after 24 h). Bigger differences were found in the biodistribution studies. NT-XII showed the highest tumor uptake as well as the best tumor to nontumor ratios.
Conclusion:
The modifications introduced in NT(8-13) increased plasma stability, maintaining unaffected the in vitro binding properties. The best biodistribution corresponded to NT-XII, which shows to be a good candidate for NT1 receptors overexpressing tumors. First clinical trials are ongoing.
Insights
Modified neurotensin analogues show promise for cancer imaging. NT-XII demonstrated superior tumor uptake and retention, making it a strong candidate for targeting neurotensin receptors in tumors.
Area of Science:
- Radiochemistry
- Oncology
- Molecular Imaging
Background:
- Neurotensin (NT) receptors are overexpressed in pancreatic and neuroendocrine cancers, presenting therapeutic and imaging targets.
- Stabilized NT analogues (NT-XII, NT-XIII, NT-XVIII) were synthesized for potential use with [(99m)Tc]-tricarbonyl labeling.
Purpose of the Study:
- To evaluate the stability, receptor binding, internalization, and biodistribution of novel stabilized neurotensin analogues.
- To identify the most promising analogue for targeting neurotensin receptor-positive tumors.
Main Methods:
- In vitro stability assays in human plasma and HT-29 cells.
- Binding affinity and internalization studies using intact HT-29 cells.
- In vivo biodistribution studies in nude mice bearing HT-29 xenografts.
Main Results:
- All analogues exhibited high plasma stability (20-21 day half-lives).
- NT-XII showed the slowest degradation in HT-29 cells and the best tumor uptake and tumor-to-nontumor ratios in vivo.
- High affinity and specificity for NT1 receptors were observed, with rapid internalization.
Conclusions:
- Modified NT analogues offer enhanced plasma stability while retaining receptor binding properties.
- NT-XII is a promising candidate for imaging and therapy of tumors overexpressing NT1 receptors.
- Clinical trials are currently underway.
