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

• DOI: 10.1007/s11095-014-1509-x
• Publication Date: 2014-09-09T21:57:48Z
• Authors: K Ganesh Kadiyala; Anupama Datta; Jyoti Tanwar; Anupriya Adhikari; B. S. Hemanth Kumar; Krishna Chuttani; Meganathan Thirumal; Anil K. Mishra
• Keywords: 0301 basic medicine; Cell Survival; Contrast Media; Mice, Nude; Magnetic Resonance Imaging; Multimodal Imaging; Large Neutral Amino Acid-Transporter 1; Molecular Imaging; 3. Good health; Heterocyclic Compounds, 1-Ring; 03 medical and health sciences; Methionine; Coordination Complexes; Predictive Value of Tests; Cell Line, Tumor; Neoplasms; Positron-Emission Tomography; Animals; Humans; Tissue Distribution; Rabbits; Radiopharmaceuticals; Cell Proliferation

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.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.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.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.