Novel DOTA-Neurotensin Analogues for 111In Scintigraphy and 68Ga PET Imaging of Neurotensin Receptor-Positive Tumors
| Autor: | Anne Gruaz-Guyon, Jacques Barbet, Sandra Mendes, Jean-Noël Talbot, Abdelhak Jallane, Faisal Al-Shoukr, Luc Brans, Aurélie Prignon, Dirk Tourwé |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Biodistribution Neurotensin receptor 1 Biomedical Engineering Pharmaceutical Science Gallium Radioisotopes Bioengineering Heterocyclic Compounds 1-Ring Mice chemistry.chemical_compound In vivo Cell Line Tumor Neoplasms Internal medicine medicine Animals Humans Receptors Neurotensin DOTA Amino Acid Sequence Neurotensin receptor Receptor neoplasms Peptide sequence Pharmacology Mice Inbred BALB C Chemistry Indium Radioisotopes Organic Chemistry Endocrinology Positron-Emission Tomography Cancer research Female Biotechnology Neurotensin |
| Zdroj: | Bioconjugate Chemistry. 22:1374-1385 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/bc200078p |
| Popis: | Overexpression of the high affinity neurotensin receptor 1 (NTSR1), demonstrated in several human cancers, has been proposed as a new marker for human ductal pancreatic carcinoma and as an independent factor for poor prognosis for ductal breast cancer, head and neck squamous cell carcinoma, and non-small cell lung cancer. The aim of the present study was to develop new DOTA-neurotensin analogues for positron emission tomography (PET) imaging with (68)Ga and for targeted radiotherapy with (90)Y or (177)Lu. We synthesized a DOTA-neurotensin analogue series. Two of these peptides bear two sequence modifications for metabolic stability: DOTA-NT-20.3 shares the same peptide sequence as the previously described DTPA-NT-20.3. In the sequence of DOTA-NT-20.4, the Arg(8)-Arg(9) bond was N-methylated instead of the Pro(7)-Arg(8) bond in DOTA-NT-20.3. An additional sequence modification was introduced in DOTA-LB119 to increase stability. A spacer was added between DOTA and the peptide sequence to increase affinity. Binding to HT29 cells, which express NTSR1, in vivo stability, and biodistribution of the various analogues were compared, and the best candidate was used to image tumors of various sizes with the microPET in mice. (111)In-DOTA-NT-20.3, in spite of a relatively high uptake in kidneys, showed specific tumor uptake and elevated tumor to other organ uptake ratios. High contrast images were obtained at early time points after injection that allowed tumor detection at a time interval postinjection appropriate for imaging with the short-lived radionuclide (68)Ga. (111)In-DOTA-NT-20.4 displayed inferior binding to HT29 cells and reduced tumor uptake. (111)In-DOTA-LB119 displayed at early time points a significantly lower renal uptake but also a lower tumor uptake than (111)In-DOTA-NT-20.3, although binding to HT29 cells was similar. (68)Ga-DOTA-NT-20.3 displayed higher tumor uptake than (68)Ga-DOTA-LB119 and allowed the detection of very small tumors by PET. In conclusion, DOTA-NT-20.3 is a promising candidate for (68)Ga-PET imaging of neurotensin receptor-positive tumors. DOTA-NT-20.3 may also be considered for therapy, as the yttrium-labeled peptide has higher affinity than that of the indium-labeled one. A prerequisite for therapeutic application of this neurotensin analogue would be to lower kidney uptake, for example, by infusion of basic amino acids, gelofusin, or albumin fragments, to prevent nephrotoxicity, as with radiolabeled somatostatin analogues. |
| Databáze: | OpenAIRE |
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