Synthesis of Specific SPECT-Radiopharmaceutical for Tumor Imaging Based on Methionine: Tc-99m-DTPA-bis(methionine)
ABSTRACT Methionine-diethylenetriaminepentaaceticacid-methionine [DTPA-bis(Met)] was synthesized by covalently conjugating two molecules of methionine (Met) to DTPA and was labeled with (99m)Tc in high radiochemical purity and specific activity (166-296 MBq/micromol). Kinetic analysis showed K(m) of 12.95 +/- 3.8 nM and a maximal transport rate velocity (V(max)) of 80.35 +/- 0.42 pmol microg protein(-1) min(-1) of (99m)Tc-DTPA-bis(Met) in U-87MG cells. DTPA-bis(Met) had dissociation constants (K(d)) of 0.067 and 0.077 nM in U-87MG and BMG, respectively. (35)S-methionine efflux was trans-stimulated by (99m)Tc-labeled DTPA conjugate demonstrating concentrative transport. The blood kinetic studies showed fast clearance with t(1/2) (F) = 36 +/- 0.5 min and t(1/2) (S) = 5 h 55 min +/- 0.85 min. U-87MG and BMG tumors saturated at approximately 2000 +/- 280 nmol/kg of (99m)Tc-DTPA-bis(Met). Initial rate of transport of (99m)Tc-DTPA-bis(Met) in U-87MG tumor was found to be 4.68 x 10(-4) micromol/kg/min. The tumor (BMG cell line, malignant glioma) grafted in athymic mice were readily identifiable in the gamma images. Semiquantitative analysis from region of interest (ROI) placed over areas counting average counts per pixel with maximum radiotracer uptake on the tumor was found to be 11.05 +/- 3.99 and compared ROI with muscle (0.55 +/- 0.13). The tumor-to-contralateral muscle tissue ratio of (99m)Tc-DTPA-bis(Met) was found to be 23 +/- 3.3. Biodistribution revealed significant tumor uptake and good contrast in the U-87MG, BMG, and EAT tumor-bearing mice. In clinical trials, the sensitivity, specificity, and positive predictive values were found to be 87.8%, 92.8%, and 96.6%, respectively. (99m)Tc-DTPA-bis(Met) showed excellent tumor targeting and has promising utility as a SPECT-radiopharmaceutical for imaging methionine-dependent human tumors and to quantify the ratio of MET(+)/HCY(-).
- SourceAvailable from: Chunhua Yang
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- "Tc-DMA complex remain at origin and free technetium rose with the solvent front in acetone (Supplemental Fig. 1) (Hazari et al., 2010; Kumar et al., 2012). "
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- "Synthesis of Au-near infrared fluorescence probe (His@Au-MPA). MPA was immobilized onto His@Au using coupling agents (EDC and NHS) to increase the reaction yield  "
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- "Retnakumari et al. have successfully synthesized folate modified Au NCs with low cytotoxicity which manifest specifically targeting capability toward oral squamous cell carcinoma (KB) with high level expression of folate receptors in tumor fluorescent imaging . Methionine (Met), which plays a crucial role in reproduction, cell survival, methylation of proteins and DNA, is indispensable for the tumor progression . Increase in the uptake of amino acid, especially methionine, is known to be one of the earliest events associated with in vitro cancerization of cells. "
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