Comparative Evaluation of the Biodistribution Profiles of a Series of Nonpeptidic Neurotensin Receptor-1 Antagonists Reveals a Promising Candidate for Theranostic Applications

Abstract

Purpose: Neurotensin receptor 1 (NTR1) is a promising target for diagnostic imaging and targeted radionuclide therapy. The aim of this study was to evaluate the biodistribution profiles of a series of newly developed diarylpyrazole-based NTR1-antagonists regarding their suitability as diagnostic and potentially radiotherapeutic agents. Methods: 3BP-227, 3BP-228 and 3BP-483 were labeled with ¹¹¹In and injected i.v. into NTR1-positive HT29 xenograft-bearing nude mice. 3, 6, 12 and 24 h after administration, single photon emission computed tomography and computed tomography (SPECT/CT) images were acquired and/or mice were sacrificed for ex vivo determination of tissue-associated radioactivity. Results: High contrast tumor visualization in SPECT/CT images was achieved using the three compounds of this study. Ex vivo biodistribution studies confirmed a high and persistent tumor uptake, peaking at 6 h p.i. for ¹¹¹In-3BP-227 (8.4±3.1 %ID/g), and at 3 h p.i. for ¹¹¹In-3BP-228 (10.2±5.3 %ID/g) and ¹¹¹In-3BP-483 (1.9±0.8 %ID/g). Tumor-to-normal tissue ratios obtained with ¹¹¹In-3BP-227 and ¹¹¹In-3BP-228 were consistently >1. Conclusion: Based on the superior biodistribution profile compared to previously reported radiolabeled NTR1 ligands, ¹¹¹In-3BP-227 is an ideal candidate for further development as a theranostic tracer.