Preclinical PET Imaging of NTSR-1-Positive Tumors with 64 Cu- and 68 Ga-DOTA-Neurotensin Analogs and Therapy with an 225 Ac-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 64 Cu or 68 Ga 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 225 Ac-di-DOTA-α,ɛ−Lys-NT(6–13). Results: 68 Ga-di-DOTA-α,ɛ−Lys-NT(6–13) was >99% stable in serum for 48 h, had an IC 50 of 5 nM using 125 I labeled NT(8–13) for binding to HT-29 cells, and high uptake in tumor models expressing NTSR-1. 68 Ga-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 225 Ac-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 68 Ga, and when radiolabeled with 225 Ac, a potent therapeutic agent.