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

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.