title: Metal based imaging probes of DO3A-Act-Met for LAT1 mediated methionine specific tumors: synthesis and preclinical evaluation.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Brig. S.K. Mazumdar Road, Delhi, 110054, India.
authors.forename: K Ganesh
authors.initials: KG
authors.lastname: Kadiyala
authors.forename: Anupama
authors.initials: A
authors.lastname: Datta
authors.forename: Jyoti
authors.initials: J
authors.lastname: Tanwar
authors.forename: Anupriya
authors.initials: A
authors.lastname: Adhikari
authors.forename: B S Hemanth
authors.initials: BS
authors.lastname: Kumar
authors.forename: Krishna
authors.initials: K
authors.lastname: Chuttani
authors.forename: Meganathan
authors.initials: M
authors.lastname: Thirumal
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D003287:Contrast Media / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000633:toxicity; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000633:toxicity; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008715:Methionine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000633:toxicity; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods*; D064847:Multimodal Imaging; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D011817:Rabbits; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000633:toxicity; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D056831:Coordination Complexes; D006573:Heterocyclic Compounds, 1-Ring; D027283:Large Neutral Amino Acid-Transporter 1; D019275:Radiopharmaceuticals; C000602438:gadolinium 2,2',2'-(10-(2-(1-carboxy-3-(methylthio)propylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; C000602439:gallium 2,2',2'-(10-(2-(1-carboxy-3-(methylthio)propylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; D008715:Methionine