Division Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig SK Mazumdar Road, Delhi-110054, India.
Bioconjug Chem. 2010 Feb 17;21(2):229-39. doi: 10.1021/bc900197n.
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(-).
蛋氨酸二乙三胺五乙酸-蛋氨酸 [DTPA-双（甲硫氨酸）] 通过将两个蛋氨酸（Met）分子与 DTPA 共价结合而合成，并以高放射化学纯度和比活度（166-296 MBq/μmol）标记（99m）Tc。动力学分析显示 U-87MG 细胞中（99m）Tc-DTPA-双（甲硫氨酸）的 K m 为 12.95±3.8 nM，最大转运速率速度（V max ）为 80.35±0.42 pmol/μg 蛋白-1 min-1。DTPA-双（甲硫氨酸）在 U-87MG 和 BMG 中的解离常数（K d ）分别为 0.067 和 0.077 nM。（35）S-蛋氨酸的外排被（99m）Tc 标记的 DTPA 缀合物反式刺激，证明是浓缩转运。血液动力学研究表明，清除速度很快，t 1/2（F）=36±0.5 min，t 1/2（S）=5 h 55 min±0.85 min。U-87MG 和 BMG 肿瘤在约 2000±280 nmol/kg 的（99m）Tc-DTPA-双（甲硫氨酸）处饱和。在 U-87MG 肿瘤中，（99m）Tc-DTPA-双（甲硫氨酸）的初始转运速率发现为 4.68×10-4μmol/kg/min。在裸鼠中移植的 U-87MG 肿瘤（BMG 细胞系，恶性神经胶质瘤）在伽马图像中很容易识别。用 ROI 放置在区域内，对每个像素的平均计数进行计数，并用肿瘤上的最大放射性示踪剂摄取进行半定量分析，发现 ROI 与肌肉（0.55±0.13）相比为 11.05±3.99。（99m）Tc-DTPA-双（甲硫氨酸）的肿瘤与对侧肌肉组织比值为 23±3.3。生物分布显示 U-87MG、BMG 和 EAT 荷瘤小鼠有明显的肿瘤摄取和良好的对比。在临床试验中，灵敏度、特异性和阳性预测值分别为 87.8%、92.8%和 96.6%。（99m）Tc-DTPA-双（甲硫氨酸）显示出优异的肿瘤靶向性，并有望作为 SPECT 放射性药物用于成像依赖蛋氨酸的人类肿瘤，并定量测定 MET（+）/HCY（-）的比值。
