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A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours

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Abstract

Purpose

Neurotensin (NT) and its high affinity receptor (NTR1) are involved in several neoplastic processes. Thus, NT-based radiopharmaceuticals are potential tracers for targeted diagnosis and therapy of NTR-positive tumours. A new analogue based on NT(8–13), NT-XIX, with the three enzymatic cleavage sites stabilised, was synthesised and tested.

Methods

The synthesis was performed by Boc strategy. Labelling with 99mTc/188Re was performed using the tricarbonyl technique. Metabolic stability was tested in vitro and in vivo. NT-XIX was further characterised in vitro in HT-29 cells and in vivo in nude mice with HT-29 xenografts.

Results

NT-XIX showed much longer half-lives than non-stabilised analogues. Binding to NTR1 was highly specific, although the affinity was lower than that of natural NT. Bound activity rapidly internalised into HT-29 cells and 50% remained trapped after 24 h. In the time-course biodistribution, the highest uptake was found in the tumour at all p.i. times. In vivo uptake was specific, and accumulation of activity in the kidneys was low. Radioactivity clearance from healthy organs was faster than that from the tumour, resulting in improved tumour-to-tissue ratios and good SPECT/CT imaging. Treatment with 188Re-NT-XIX (30 MBq, in three or four fractions) decreased tumour growth by 50% after 3 weeks.

Conclusion

The high in vivo stability and the favourable in vivo behaviour makes NT-XIX an excellent candidate for the imaging and therapy of NTR1-positive tumours.

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Acknowledgements

We thank the Fund for Scientific Research-Flanders Belgium (contract No. G.0036.04) for financial support, Ms. Harriet Struthers for her assistance with editing the manuscript and Ms. Margaretha Lutz for her technical help.

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Authors and Affiliations

  1. Paul Scherrer Institute, Center for Radiopharmaceutical Science, CH-5232, Villigen PSI, Switzerland

    Elisa García-Garayoa, Peter Bläuenstein, Alain Blanc & P. August Schubiger

  2. Department of Organic Chemistry, Vrije Universiteit Brussels, Pleinlaan 2, 1050, Brussels, Belgium

    Veronique Maes & Dirk Tourwé

  3. Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang-Pauli Strasse 10, CH-8093, Zurich, Switzerland

    P. August Schubiger

Authors
  1. Elisa García-Garayoa
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  2. Peter Bläuenstein
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  5. Dirk Tourwé
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Corresponding author

Correspondence to Elisa García-Garayoa.

Additional information

This work was partly funded by the Fund for Scientific Research-Flanders (Belgium), contract No. G.0036.04.

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García-Garayoa, E., Bläuenstein, P., Blanc, A. et al. A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours. Eur J Nucl Med Mol Imaging 36, 37–47 (2009). https://doi.org/10.1007/s00259-008-0894-y

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  • DOI: https://doi.org/10.1007/s00259-008-0894-y

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