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

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. A di-DOTA analog of NT(6-13) with three unnatural amino acids was synthesized and radiolabeled with either Cu or 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 Ac-di-DOTA-α,ɛ-Lys-NT(6-13). Ga-di-DOTA-α,ɛ-Lys-NT(6-13) was >99% stable in serum for 48 h, had an IC of 5 nM using I labeled NT(8-13) for binding to HT-29 cells, and high uptake in tumor models expressing NTSR-1. Ga-di-DOTA-α,ɛ-Lys-NT(6-13) had an average %ID/g ( = 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-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. 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 Ga, and when radiolabeled with Ac, a potent therapeutic agent.