Metal Based Imaging Probes of DO3A-Act-Met for LAT1 Mediated Methionine Specific Tumors: Synthesis and Preclinical Evaluation

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2014 Sep 11

PMID 25205462

Authors

K Ganesh Kadiyala

Anupama Datta

Jyoti Tanwar

Anupriya Adhikari

B S Hemanth Kumar

Krishna Chuttani

Meganathan Thirumal

Anil K Mishra

Affiliations

Soon will be listed here.

Abstract

Purpose: Tumor cells are known to have an elevated requirement for methionine due to increased protein synthesis and trans-methylation reactions. A methionine based macrocyclic tumor imaging system, DO3A-Act-Met, has been designed to provide a novel platform for tumor imaging via modalities, PET/MRI using metal ions, (68)Ga and (157)Gd.

Methods: Synthesis of DO3A-Act-Met was confirmed through NMR and mass spectrometric techniques. Cytotoxicity of complexes was evaluated using MTT assay whereas receptor binding and trans-stimulation studies were performed on EAT and U-87 MG cell lines. Tumor targeting was assessed through imaging and biodistribution experiments on U-87 MG xenograft model.

Results: DO3A-Act-Met was synthesized and radiolabeled with (68)Ga in high radiochemical purity (85-92%). The receptor binding assay on EAT cells predicted high binding affinity with Kd of 0.78 nM. Efflux of (35)S-L-methionine trans-stimulated by extracellular DO3A-Act-Met on U-87MG cells suggested an L-system transport. MR studies revealed a longitudinal relaxivity of 4.35 mM(-1) s(-1) for Gd-DO3A-Act-Met and a 25% signal enhancement at tumor site. The biodistribution studies in U-87MG xenografts validated tumor specificity.

Conclusion: DO3A-Act-Met, a methionine conjugated probe is a promising agent for targeted molecular imaging, exhibiting high specificity towards tumor owing to its essential role in proliferation of cancer cells mediated through LAT1.

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