Preclinical PET Imaging of NTSR-1-Positive Tumors with 64Cu- and 68Ga-DOTA-Neurotensin Analogs and Therapy with an 225Ac-DOTA-Neurotensin Analog.

Abstract

Background: The aim of the study was to perform PET imaging and radiotherapy with a novel neurotensin derivative for neurotensin receptor 1 (NTSR-1)-positive tumors in an animal model. Materials and Methods: A di-DOTA analog of NT(6-13) with three unnatural amino acids was synthesized and radiolabeled with either 64Cu or 68Ga and tested for serum stability and tumor imaging in mice bearing NTSR-1-positive PC3, and HT29 xenografts. A dose-response therapy study was performed with 18.5, 37, and 74 kBq of 225Ac-di-DOTA-α,ɛ-Lys-NT(6-13). Results: 68Ga-di-DOTA-α,ɛ-Lys-NT(6-13) was >99% stable in serum for 48 h, had an IC50 of 5 nM using 125I labeled NT(8-13) for binding to HT-29 cells, and high uptake in tumor models expressing NTSR-1. 68Ga-di-DOTA-α,ɛ-Lys-NT(6-13) had an average %ID/g (n = 4) at 2 h of 4.0 for tumor, 0.5 for blood, 12.0 for kidney, and <1 for other tissues, resulting in a favorable T/B of 8. Mean survivals of tumor-bearing mice treated with 18.5 or 37 kBq of 225Ac-di-DOTA-α,ɛ-Lys-NT(6-13) were 81 and 93 d, respectively, versus 53 d for controls. Whole-body toxicity was seen for the 74 kBq dose. Conclusions: Based on the results of the animal model, di-DOTA-α,ɛ-Lys-NT(6-13) is a useful imaging agent for NTSR-1-positive tumors when radiolabeled with 68Ga, and when radiolabeled with 225Ac, a potent therapeutic agent.

• Authors: Daneng Li, Megan Minnix, Rebecca Allen, James Bading, Junie Chea, Patty Wong, Nicole Bowles, Erasmus Poku, John E Shively
• Journal: Cancer biotherapy & radiopharmaceuticals (Cancer Biother Radiopharm) Vol. 36 Issue 8 Pg. 651-661 (Oct 2021) ISSN: 1557-8852 [Electronic] United States
• PMID: 32822229 (Publication Type: Journal Article)

Chemical References

• Chelating Agents
• Gallium Radioisotopes
• Heterocyclic Compounds, 1-Ring
• Receptors, Neurotensin
• neurotensin type 1 receptor
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• Neurotensin

Topics

• Animals
• Chelating Agents (pharmacology)
• Disease Models, Animal
• Gallium Radioisotopes
• HT29 Cells
• Heterocyclic Compounds, 1-Ring (pharmacology)
• Heterografts
• Humans
• Mice
• Neoplasms (diagnostic imaging, metabolism, therapy)
• Neurotensin (analogs & derivatives, metabolism)
• Outcome Assessment, Health Care
• Positron-Emission Tomography (methods)
• Receptors, Neurotensin (metabolism)