LAT1 Targeted Delivery of Methionine Based Imaging Probe Derived from M(III) Metal Ions for Early Diagnosis of Proliferating Tumours using Molecular Imaging Modalities

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-1of Gd(III)-DTPA-bis(Met) were observed at pH 7.4 at 7T. Bright, localized fluorescence of Eu(III)-DTPA-bis(Met) was observed with standard microscopy and displacement studies indicated ligand functionality. KD value determined for Eu(III)-DTPA-bis(Met) on U-87MG 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-87MG 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.