title: LAT1 targeted delivery of methionine based imaging probe derived from M(III) metal ions for early diagnosis of proliferating tumours using molecular imaging modalities.
abstract: We investigated the potential of DTPA-bis(Methionine), a target specific amino acid based probe for detection of L-type amino acid transporters (LAT1) known to over express in proliferating tumours using multimodality imaging. The ligand, DTPA-bis(Met) was readily converted to lanthanide complexes and was found capable of targeting cancer cells using multimodality imaging. DTPA-bis(Met) complexes were synthesized and characterized by mass spectroscopy. MR longitudinal relaxivity, r₁ = 4.067 ± 0.31 mM⁻¹s⁻¹ and transverse relaxivity, r₂ = 8.61 ± 0.07 mM⁻¹s⁻¹ of Gd(III)-DTPA-bis(Met) were observed at pH 7.4 at 7 T. Bright, localized fluorescence of Eu(III)-DTPA-bis(Met) was observed with standard microscopy and displacement studies indicated ligand functionality. K(D) value determined for Eu(III)-DTPA-bis(Met) on U-87 MG cells was found to be 17.3 pM and showed appreciable fluorescence within the cells. Radio HPLC showed a radiochemical purity more than 95% (specific activity = 400-500 MBq/μmol, labelling efficiency 78 %) for ⁶⁸Ga(III)-DTPA-bis(Met). Pre-treatment of xenografted U-87 MG athymic mice with ⁶⁸Ga(III)-DTPA-bis(Met) following unlabelled L-methionine administration reduced tumour uptake by 10-folds in Micro PET. These data support the specific binding of ⁶⁸Ga(III)-DTPA-bis(Met) to the LAT1 transporter. To summarize, this agent possesses high stability in biological environment and exhibits effective interaction with its LAT1 transporters giving high accumulation in tumour area, excellent tumour/non-tumour ratio and low non-specific retention in vivo.
authors.forename: Puja Panwar
authors.initials: PP
authors.lastname: Hazari
authors.forename: Surbhi
authors.initials: S
authors.lastname: Prakash
authors.forename: Virendra K
authors.initials: VK
authors.lastname: Meena
authors.forename: Ambika
authors.initials: A
authors.lastname: Jaswal
authors.forename: Harleen
authors.initials: H
authors.lastname: Khurana
authors.forename: Surabhi Kirti
authors.initials: SK
authors.lastname: Mishra
authors.forename: Hemanth Kumar
authors.initials: HK
authors.lastname: Bhonsle
authors.forename: Lokendra
authors.initials: L
authors.lastname: Singh
authors.affiliation: Scientist G, Additional Director, Brig. S. K. Mazumdar Road, Delhi-110054, India. akmishra63@gmail.com.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056831:Coordination Complexes / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D055088:Early Detection of Cancer; D005260:Female; D005710:Gallium Radioisotopes; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008715:Methionine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D057054:Molecular Imaging / Q000009:adverse effects; D064847:Multimodal Imaging; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D004369:Pentetic Acid / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D011817:Rabbits; D011877:Radionuclide Imaging; D051381:Rats; D017208:Rats, Wistar
chemical_list: C000601124:68Ga(III)-DTPA-bis(Met); D056831:Coordination Complexes; D005710:Gallium Radioisotopes; D027283:Large Neutral Amino Acid-Transporter 1; D008024:Ligands; D009363:Neoplasm Proteins; D004369:Pentetic Acid; D008715:Methionine