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

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 Cu-64 or Ga-68 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 Ac-225-di-DOTA-alpha,e-Lys-NT(6-13).

Results: Ga-68-di-DOTA-alpha,e-Lys-NT(6-13) was >99% stable in serum for 48 h, had an IC50 of 5 nM using I-125 labeled NT(8-13) for binding to HT-29 cells, and high uptake in tumor models expressing NTSR-1. Ga-68-di-DOTA-alpha,e-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 Ac-225-di-DOTA-alpha,e-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-alpha,e-Lys-NT(6-13) is a useful imaging agent for NTSR-1-positive tumors when radiolabeled with Ga-68, and when radiolabeled with Ac-225, a potent therapeutic agent.