Preparation and Preliminary Biological Evaluation of Novel 99mTc-Labelled Thymidine Analogs as Tumor Imaging Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry and Radiolabeling
2.2. In vitro Stability and Octanol-Water Partition Coefficient
Constituent | pH = 7.0 | pH = 7.4 |
---|---|---|
99mTc-TMHEA | 1.01 ± 0.03 | 1.06 ± 0.02 |
99mTc-TMHHA | 0.99 ± 0.01 | 1.02 ± 0.03 |
2.3. Blood Kinetics Studies
Parameters | 99mTc-TMHEA | 99mTc-TMHHA |
---|---|---|
K12 (min−1) | 0.033 | 0.101 |
K21 (min−1) | 0.035 | 0.082 |
Ke (min−1) | 0.032 | 0.035 |
CL (%ID/g/min) | 0.098 | 0.086 |
T1/2α (min) | 6.785 | 3.234 |
T1/2β (min) | 36.029 | 33.448 |
AUC (%ID/g/min) | 162.658 | 186.894 |
2.4. Biodistribution Studies
Tissue | Time (min) | ||||||
---|---|---|---|---|---|---|---|
5 | 10 | 15 | 30 | 60 | 120 | 180 | |
99mTc-TMHEA | |||||||
Brain | 0.27 ± 0.01 | 0.24 ± 0.07 | 0.20 ± 0.04 | 0.13 ± 0.07 | 0.04 ± 0.01 | 0.02 ± 0.01 | 0.02 ± 0.00 |
Heart | 3.61 ± 0.14 | 2.32 ± 0.63 | 2.04 ± 0.11 | 1.01 ± 0.46 | 0.42±0.07 | 0.23 ± 0.04 | 0.18 ± 0.03 |
Liver | 5.71 ± 0.81 | 4.83±0.87 | 5.22 ± 0.86 | 4.25 ± 0.36 | 4.17 ± 0.19 | 2.72 ± 0.44 | 3.27 ± 0.18 |
Spleen | 2.42 ± 0.03 | 1.69 ± 0.59 | 1.62 ± 0.09 | 1.06 ± 0.34 | 0.79 ± 0.15 | 0.81 ± 0.30 | 0.79 ± 0.21 |
Lung | 5.59 ± 0.73 | 4.15 ± 0.48 | 4.53 ± 0.95 | 2.30 ± 0.66 | 1.45 ± 0.20 | 1.50 ± 0.46 | 0.95 ± 0.22 |
Kidney | 23.99 ± 0.79 | 15.50 ± 0.42 | 14.20 ± 0.50 | 12.45 ± 0.81 | 10.22 ± 0.74 | 8.87 ± 0.44 | 9.32 ± 0.24 |
Tumor | 2.51 ± 0.28 | 2.00 ± 0.53 | 1.94 ± 0.31 | 1.34 ± 0.24 | 0.62 ± 0.12 | 0.51 ± 0.05 | 0.48 ± 0.07 |
Stomach | 1.57 ± 0.58 | 1.17 ± 0.37 | 1.35 ± 0.24 | 0.73 ± 0.12 | 0.47 ± 0.12 | 1.82 ± 0.79 | 1.17 ± 0.29 |
S. intestines | 3.82 ± 0.99 | 3.16 ± 0.57 | 2.90 ± 0.10 | 2.45 ± 0.36 | 2.36 ± 0.41 | 2.31 ± 0.03 | 1.98 ± 0.28 |
Bladder | 14.18 ± 0.87 | 12.29 ± 0.52 | 10.51 ± 0.55 | 7.09 ± 0.04 | 4.24 ± 0.38 | 1.56 ± 0.62 | 1.17 ± 0.87 |
Muscle | 1.93 ± 0.16 | 1.31 ± 0.41 | 1.55 ± 0.56 | 0.66 ± 0.15 | 0.38 ± 0.06 | 0.22 ± 0.08 | 0.14 ± 0.05 |
Bone | 2.02 ± 0.14 | 1.30 ± 0.48 | 1.57 ± 0.52 | 0.87 ± 0.16 | 0.63 ± 0.23 | 0.51 ± 0.17 | 0.33 ± 0.15 |
Blood | 3.86 ± 0.60 | 2.77 ± 0.91 | 2.48 ± 0.73 | 1.02 ± 0.25 | 0.48 ± 0.09 | 0.29 ± 0.05 | 0.29 ± 0.06 |
Tumor/Muscle | 1.30 ± 0.04 | 1.54 ± 0.08 | 1.56 ± 0.02 | 1.98 ± 0.21 | 1.85 ± 0.02 | 2.84 ± 0.76 | 2.98 ± 0.37 |
Tumor/Bone | 1.24 ± 0.06 | 1.59 ± 0.22 | 1.51 ± 0.03 | 1.46 ± 0.17 | 1.14 ± 0.12 | 1.27 ± 0.20 | 1.62 ± 0.18 |
Tumor/Blood | 0.65 ± 0.03 | 0.78 ± 0.12 | 0.93 ± 0.01 | 1.21 ± 0.07 | 1.27 ± 0.22 | 1.87 ± 0.02 | 1.80 ± 0.41 |
99mTc-TMHHA | |||||||
Brain | 0.27 ± 0.02 | 0.25 ± 0.03 | 0.20 ± 0.04 | 0.13 ± 0.04 | 0.11 ± 0.04 | 0.03 ± 0.00 | 0.03 ± 0.00 |
Heart | 3.01 ± 0.29 | 2.44 ± 0.10 | 1.79 ± 0.42 | 1.10 ± 0.30 | 0.96 ± 0.09 | 0.25 ± 0.05 | 0.23 ± 0.03 |
Liver | 8.79 ± 0.60 | 8.21 ± 0.30 | 8.08 ± 0.66 | 5.43 ± 0.01 | 5.39 ± 0.28 | 4.43 ± 0.83 | 4.13 ± 0.34 |
Spleen | 2.41 ± 0.30 | 2.13 ± 0.47 | 1.84 ± 0.43 | 1.42 ± 0.17 | 1.19 ± 0.20 | 0.83 ± 0.17 | 0.90 ± 0.13 |
Lung | 4.55 ± 0.77 | 4.42 ± 0.04 | 2.96 ± 0.43 | 2.04 ± 0.48 | 1.76 ± 0.55 | 0.86 ± 0.15 | 0.75 ± 0.34 |
Kidney | 15.38 ± 0.52 | 14.14 ± 0.95 | 9.46 ± 0.19 | 7.65 ± 0.39 | 5.83 ± 0.45 | 3.00 ± 0.74 | 3.27 ± 0.36 |
Tumor | 2.38 ± 0.41 | 2.23 ± 0.60 | 1.43 ± 0.20 | 1.26 ± 0.12 | 0.88 ± 0.22 | 0.42 ± 0.12 | 0.41 ± 0.10 |
Stomach | 1.55 ± 0.32 | 1.52 ± 0.43 | 0.81 ± 0.20 | 0.80 ± 0.16 | 0.62 ± 0.18 | 0.50 ± 0.20 | 0.46 ± 0.08 |
S. intestines | 5.97 ± 0.79 | 5.73 ± 0.01 | 4.32 ± 0.42 | 4.00 ± 0.19 | 2.06 ± 0.21 | 0.89 ± 0.35 | 0.85 ± 0.17 |
Bladder | 16.05 ± 0.95 | 14.47 ± 0.32 | 8.66 ± 0.98 | 4.95 ± 0.27 | 2.82 ± 0.56 | 1.43 ± 0.35 | 1.05 ± 0.06 |
Muscle | 1.75 ± 0.21 | 1.67 ± 0.43 | 1.00 ± 0.23 | 0.65 ± 0.17 | 0.49 ± 0.20 | 0.17 ± 0.04 | 0.14 ± 0.02 |
Bone | 2.27 ± 0.67 | 2.20 ± 0.53 | 1.71 ± 0.65 | 0.99 ± 0.21 | 0.79 ± 0.14 | 0.47 ± 0.14 | 0.52 ± 0.05 |
Blood | 3.81 ± 0.47 | 3.37 ± 0.14 | 2.12 ± 0.52 | 1.14 ± 0.31 | 0.83 ± 0.22 | 0.31 ± 0.06 | 0.27 ± 0.03 |
Tumor/Muscle | 1.36 ± 0.15 | 1.35 ± 0.18 | 1.34 ± 0.21 | 1.60 ± 0.08 | 1.62 ± 0.12 | 2.42 ± 0.33 | 2.46 ± 0.24 |
Tumor/Bone | 1.09 ± 0.20 | 1.07 ± 0.12 | 1.06 ± 0.11 | 1.03 ± 0.06 | 0.98 ± 0.05 | 0.90 ± 0.16 | 0.81 ± 0.28 |
Tumor/Blood | 0.72 ± 0.10 | 0.74 ± 0.09 | 0.67 ± 0.12 | 0.96 ± 0.04 | 1.07 ± 0.05 | 1.28 ± 0.22 | 1.34 ± 0.08 |
2.5. Abnormal Toxicity Test
3. Experimental
3.1. General
3.2. Synthesis of 99mTc-TMHEA and 99mTc-TMHHA
3.2.1. General Procedure for the Preparation of Compounds 1a and 1b
3.2.2. General Procedure for the Preparation of Compounds 2a and 2b
3.2.3. General Procedure for the Preparation of Compounds 3a and 3b
3.2.4. General Procedure for the Preparation of Compounds 4a and 4b
3.2.5. General Procedure for the preparation of compounds 5a and 5b
3.2.6. General Procedure for the Preparation of Compounds 6a and 6b
3.2.7. General Procedure for the Preparation of Compounds 7a and 7b
3.3. Radiochemical Syntheses of 99mTc-TMHEA (8a) and 99mTc-TMHHA (8b)
3.4. Quality Control of 99mTc-TMHEA and 99mTc-TMHHA
3.4.1. TLC
3.4.2. HPLC
3.5. In Vitro Stability of 99mTc-TMHEA and 99mTc-TMHHA
3.6. Octanol-Water Partition Coefficients of 99mTc-TMHEA and 99mTc-TMHHA
3.7. Tumor Models
3.8. Biodistribution in Tumor-Bearing Mice of 99mTc-TMHEA and 99mTc-TMHHA
4. Conclusions
Acknowledgments
References
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Lu, C.; Jiang, Q.; Tan, C.; Tang, J.; Zhang, J. Preparation and Preliminary Biological Evaluation of Novel 99mTc-Labelled Thymidine Analogs as Tumor Imaging Agents. Molecules 2012, 17, 8518-8532. https://doi.org/10.3390/molecules17078518
Lu C, Jiang Q, Tan C, Tang J, Zhang J. Preparation and Preliminary Biological Evaluation of Novel 99mTc-Labelled Thymidine Analogs as Tumor Imaging Agents. Molecules. 2012; 17(7):8518-8532. https://doi.org/10.3390/molecules17078518
Chicago/Turabian StyleLu, Chunxiong, Quanfu Jiang, Cheng Tan, Jie Tang, and Jiankang Zhang. 2012. "Preparation and Preliminary Biological Evaluation of Novel 99mTc-Labelled Thymidine Analogs as Tumor Imaging Agents" Molecules 17, no. 7: 8518-8532. https://doi.org/10.3390/molecules17078518