Chem. J. Chinese Universities ›› 2015, Vol. 36 ›› Issue (12): 2446.doi: 10.7503/cjcu20150388
• Organic Chemistry • Previous Articles Next Articles
YU Qian1, HE Yingfang1, CHEN Yuan1, YANG Wenjiang2, ZHANG Chun3, LU Jie1,*(
)
Received:2015-05-14
Online:2015-12-10
Published:2015-11-17
Contact:
LU Jie
E-mail:ljie74@bnu.edu.cn
Supported by:TrendMD:
YU Qian, HE Yingfang, CHEN Yuan, YANG Wenjiang, ZHANG Chun, LU Jie. Preparation and Biological Evaluation of 99mTc-labeled Pteroyl-lys Derivatives†[J]. Chem. J. Chinese Universities, 2015, 36(12): 2446.
Scheme 1 Synthesis of conjugates Pteroyl-lys-penta-HYNIC(6) and Pteroyl-lys-Gly-Gly-HYNIC(7) a. DCC, DMSO/pyridine, r.t., overnight; b. TFA, 0 ℃, 8 h; c. NHS-HYNIC, DMSO/pyridine, r.t., 24 h.
| Compd. | Appearance | Yield(%) | ESI-MS,m/z[M+H]+ | HRMS,m/z[M+H]+ |
|---|---|---|---|---|
| 1 | Yellow powder | 55 | 640.9(640.3) | |
| 2 | Yellow powder | 50 | 540.5(540.3) | |
| 3 | Pale yellow powder | 70 | 329.9(329.1) | |
| 4 | Yellow powder | 49 | 655.5(655.3) | |
| 5 | Yellow powder | 51 | 555.3(555.2) | |
| 6 | Yellow powder | 54 | 806.4(806.4) | 806.3834(806.3856) |
| 7 | Yellow powder | 50 | 821.5(821.4) | 821.3597(821.3591) |
Table 1 Appearance, yields, ESI-MS and HRMS data for compounds 1—7
| Compd. | Appearance | Yield(%) | ESI-MS,m/z[M+H]+ | HRMS,m/z[M+H]+ |
|---|---|---|---|---|
| 1 | Yellow powder | 55 | 640.9(640.3) | |
| 2 | Yellow powder | 50 | 540.5(540.3) | |
| 3 | Pale yellow powder | 70 | 329.9(329.1) | |
| 4 | Yellow powder | 49 | 655.5(655.3) | |
| 5 | Yellow powder | 51 | 555.3(555.2) | |
| 6 | Yellow powder | 54 | 806.4(806.4) | 806.3834(806.3856) |
| 7 | Yellow powder | 50 | 821.5(821.4) | 821.3597(821.3591) |
| Compd. | 1H NMR(DMSO-d6, 400 MHz), δ | 13C NMR(DMSO-d6, 400 MHz), δ |
|---|---|---|
| 1 | 1.33—1.36(m, 2H), 1.39(s, 9H), 1.41—1.43(m, 2H), 1.74(s, 2H), 2.00(t, 2H), 2.54(s, 2H), 2.86—2.89(m, 4H), 2.99—3.00(m, 2H), 4.28(t, 1H), 4.48—4.49(m, 2H), 6.64(d, 2H,J=7.5 Hz), 7.66(d, 2H, J=8.6 Hz), 8.64(s, 1H) | |
| 2 | 1.38(m, 4H), 1.50(m, 4H), 1.74(m, 2H), 2.06(m, 2H), 2.76(m, 2H), 3.02(m, 2H), 4.30(m, 1H), 4.50(s, 2H), 6.64(d, 2H, J=8.3 Hz), 7.66(d, 2H, J=8.4 Hz), 8.66(s, 1H) | |
| 3* | 1.45(s, 9H), 2.85(s, 4H), 3.88(d, 2H), 4.43(d, 2H) | |
| 4 | 1.37(s, 9H), 1.74(m, 2H), 2.54(m, 4H), 3.03—3.04(m, 2H), 3.55(d, 2H), 3.64(d, 2H), 4.24—4.30(m, 1H), 4.48(d, 2H), 6.64(d, 2H, J=8.7 Hz), 7.66(d, 2H, J=8.7 Hz), 8.65(s, 1H) | |
| 5 | 1.21(m, 2H), 1.31(m, 2H), 1.64(m, 2H), 4.09(m, 5H), 4.41(m 6H), 6.58(d, 2H), 7.58(d, 2H), 8.57(s, 1H) | |
| 6 | 1.38(m, 3H), 1.49(m, 2H), 1.75(m, 2H), 1.90(m, 1H), 2.06(m, 1H), 2.50(m, 3H), 2.74(m, 1H), 2.93(m, 6H), 3.21(m, 3H), 4.29(s, 1H), 4.49(s, 2H), 6.65(d, 2H), 6.92(m, 3H), 7.49(s, 1H), 7.67(m, 3H), 8.04(m, 2H), 8.65(m, 2H) | 20.99, 22.89, 23.25, 28.75, 28.88, 30.37, 35.12, 38.18, 45.91, 52.38, 104.74, 111.17, 111.91, 120.32, 121.41, 127.46, 127.88, 128.94, 131.10, 136.76, 141.81, 148.52, 150.70, 153.81, 158.45, 161.07, 164.83, 166.37, 167.36, 171.97, 174.19 |
| 7 | 1.34(m, 4H), 1.72(m, 2H), 2.71(m, 2H), 2.93(m, 4H), 3.03(m, 2H), 3.84(m, 3H), 4.24(m, 2H), 4.46(s, 2H), 6.62(d, 2H), 6.94(m, 3H), 7.65(m, 3H), 8.04(m, 3H), 8.63(m, 2H) | 23.19, 28.67, 30.46, 38.35, 40.41, 42.06, 42.86, 45.91, 52.43, 104.76, 111.71, 177.78, 119.60, 121.47, 122.51, 127.51, 128.93, 131.07, 136.94, 142.03, 147.91, 148.51, 150.70, 151.91, 153.85, 156.21, 160.81, 165.61, 166.33, 167.34, 168.49, 169.44 |
Table 2 1H NMR and 13C NMR data for compounds 1—7
| Compd. | 1H NMR(DMSO-d6, 400 MHz), δ | 13C NMR(DMSO-d6, 400 MHz), δ |
|---|---|---|
| 1 | 1.33—1.36(m, 2H), 1.39(s, 9H), 1.41—1.43(m, 2H), 1.74(s, 2H), 2.00(t, 2H), 2.54(s, 2H), 2.86—2.89(m, 4H), 2.99—3.00(m, 2H), 4.28(t, 1H), 4.48—4.49(m, 2H), 6.64(d, 2H,J=7.5 Hz), 7.66(d, 2H, J=8.6 Hz), 8.64(s, 1H) | |
| 2 | 1.38(m, 4H), 1.50(m, 4H), 1.74(m, 2H), 2.06(m, 2H), 2.76(m, 2H), 3.02(m, 2H), 4.30(m, 1H), 4.50(s, 2H), 6.64(d, 2H, J=8.3 Hz), 7.66(d, 2H, J=8.4 Hz), 8.66(s, 1H) | |
| 3* | 1.45(s, 9H), 2.85(s, 4H), 3.88(d, 2H), 4.43(d, 2H) | |
| 4 | 1.37(s, 9H), 1.74(m, 2H), 2.54(m, 4H), 3.03—3.04(m, 2H), 3.55(d, 2H), 3.64(d, 2H), 4.24—4.30(m, 1H), 4.48(d, 2H), 6.64(d, 2H, J=8.7 Hz), 7.66(d, 2H, J=8.7 Hz), 8.65(s, 1H) | |
| 5 | 1.21(m, 2H), 1.31(m, 2H), 1.64(m, 2H), 4.09(m, 5H), 4.41(m 6H), 6.58(d, 2H), 7.58(d, 2H), 8.57(s, 1H) | |
| 6 | 1.38(m, 3H), 1.49(m, 2H), 1.75(m, 2H), 1.90(m, 1H), 2.06(m, 1H), 2.50(m, 3H), 2.74(m, 1H), 2.93(m, 6H), 3.21(m, 3H), 4.29(s, 1H), 4.49(s, 2H), 6.65(d, 2H), 6.92(m, 3H), 7.49(s, 1H), 7.67(m, 3H), 8.04(m, 2H), 8.65(m, 2H) | 20.99, 22.89, 23.25, 28.75, 28.88, 30.37, 35.12, 38.18, 45.91, 52.38, 104.74, 111.17, 111.91, 120.32, 121.41, 127.46, 127.88, 128.94, 131.10, 136.76, 141.81, 148.52, 150.70, 153.81, 158.45, 161.07, 164.83, 166.37, 167.36, 171.97, 174.19 |
| 7 | 1.34(m, 4H), 1.72(m, 2H), 2.71(m, 2H), 2.93(m, 4H), 3.03(m, 2H), 3.84(m, 3H), 4.24(m, 2H), 4.46(s, 2H), 6.62(d, 2H), 6.94(m, 3H), 7.65(m, 3H), 8.04(m, 3H), 8.63(m, 2H) | 23.19, 28.67, 30.46, 38.35, 40.41, 42.06, 42.86, 45.91, 52.43, 104.76, 111.71, 177.78, 119.60, 121.47, 122.51, 127.51, 128.93, 131.07, 136.94, 142.03, 147.91, 148.51, 150.70, 151.91, 153.85, 156.21, 160.81, 165.61, 166.33, 167.34, 168.49, 169.44 |
Fig.1 Radioactive HPLC profiles of 99mTc(HYNIC-penta-lys-Pteroyl)(Tricine/TPPTS) in saline at 0 h(A) and 4 h(B), and mouse plasma stability after 4 h incubation at 37 ℃(C) The retention time of 99mTc(HYNIC-penta-lys-Pteroyl)(Tricine/TPPTS) was 23.3 min.
Fig.2 Radioactive HPLC profiles of 99mTc(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS) in saline at 0 h(A) and 4 h(B), and mouse plasma stability after 4 h incubation at 37 ℃(C) The retention time of 99mTc(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS) was 22.6 min.
Fig.3 Cellular binding of 99mTc(HYNIC-penta-lys-Pteroyl)(Tricine/TPPTS)(A) and 99mTc(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS)(B) in KB tumor cells at 37 ℃ The cell total binding fractions(●), cell internalized fractions(■) and blocked by excess folic acid(▲) were expressed in relation to the total added activity(%, of total activity added).
| Sample | Biodistribution/(%ID·g-1) | ||||
|---|---|---|---|---|---|
| 1 h | 2 h | 2 h(Blockade) | 2 h(PMX) | 4 h | |
| Heart | 1.37±0.06 | 1.79±0.29 | 0.36±0.13 | 1.22±0.15 | 1.32±0.52 |
| Liver | 2.09±0.60 | 2.00±0.64 | 0.97±0.05 | 2.10±0.26 | 1.78±0.17 |
| Spleen | 0.80±0.28 | 0.44±0.14 | 0.34±0.04 | 0.65±0.11 | 0.41±0.20 |
| Lung | 1.80±0.28 | 1.38±0.41 | 1.05±0.57 | 1.18±0.51 | 1.04±0.44 |
| Kidney | 105.91±12.73 | 112.80±7.00 | 18.52±0.69a | 44.11±6.89b | 127.93±18.34 |
| Bone | 0.60±0.21 | 0.34±0.27 | 0.65±0.88 | 1.55±0.82 | 0.36±0.24 |
| Muscle | 1.44±0.19 | 1.93±0.30 | 0.97±1.34 | 1.73±0.72 | 1.92±0.43 |
| Stomach | 1.25±0.61 | 1.40±0.50 | 1.23±0.40 | 0.58±0.09 | 1.03±0.40 |
| Intestine | 1.28±0.09 | 1.31±0.54 | 2.17±0.43 | 1.41±0.28 | 1.28±0.04 |
| Tumor | 8.55±2.78 | 8.83±0.42 | 1.64±0.49a | 10.02±2.88 | 7.99±2.28 |
| Blood | 0.83±0.12 | 0.29±0.14 | 0.73±0.19 | 0.43±0.13 | 0.15±0.05 |
| Ratio of tumor/muscle | 5.94 | 4.58 | 5.80 | 4.15 | |
| Ratio of tumor/blood | 10.26 | 30.07 | 23.14 | 54.90 | |
| Ratio of tumor/kidney | 0.08 | 0.08 | 0.23 | 0.06 | |
| Ratio of tumor/liver | 4.09 | 4.41 | 4.76 | 4.48 | |
Table 3 Biodistribution of 99mTc(HYNIC-penta-lys-Pteroyl)(Tricine/TPPTS) in KB tumor-bearing mice(n=5)
| Sample | Biodistribution/(%ID·g-1) | ||||
|---|---|---|---|---|---|
| 1 h | 2 h | 2 h(Blockade) | 2 h(PMX) | 4 h | |
| Heart | 1.37±0.06 | 1.79±0.29 | 0.36±0.13 | 1.22±0.15 | 1.32±0.52 |
| Liver | 2.09±0.60 | 2.00±0.64 | 0.97±0.05 | 2.10±0.26 | 1.78±0.17 |
| Spleen | 0.80±0.28 | 0.44±0.14 | 0.34±0.04 | 0.65±0.11 | 0.41±0.20 |
| Lung | 1.80±0.28 | 1.38±0.41 | 1.05±0.57 | 1.18±0.51 | 1.04±0.44 |
| Kidney | 105.91±12.73 | 112.80±7.00 | 18.52±0.69a | 44.11±6.89b | 127.93±18.34 |
| Bone | 0.60±0.21 | 0.34±0.27 | 0.65±0.88 | 1.55±0.82 | 0.36±0.24 |
| Muscle | 1.44±0.19 | 1.93±0.30 | 0.97±1.34 | 1.73±0.72 | 1.92±0.43 |
| Stomach | 1.25±0.61 | 1.40±0.50 | 1.23±0.40 | 0.58±0.09 | 1.03±0.40 |
| Intestine | 1.28±0.09 | 1.31±0.54 | 2.17±0.43 | 1.41±0.28 | 1.28±0.04 |
| Tumor | 8.55±2.78 | 8.83±0.42 | 1.64±0.49a | 10.02±2.88 | 7.99±2.28 |
| Blood | 0.83±0.12 | 0.29±0.14 | 0.73±0.19 | 0.43±0.13 | 0.15±0.05 |
| Ratio of tumor/muscle | 5.94 | 4.58 | 5.80 | 4.15 | |
| Ratio of tumor/blood | 10.26 | 30.07 | 23.14 | 54.90 | |
| Ratio of tumor/kidney | 0.08 | 0.08 | 0.23 | 0.06 | |
| Ratio of tumor/liver | 4.09 | 4.41 | 4.76 | 4.48 | |
| Sample | Biodistribution/(%ID·g-1) | ||||
|---|---|---|---|---|---|
| 1 h | 2 h | 2 h(Blockade) | 2 h(PMX) | 4 h | |
| Heart | 3.06±0.90 | 3.45±1.04 | 0.44±0.26 | 2.52±0.48 | 2.89±0.68 |
| Liver | 3.73±0.55 | 3.87±1.57 | 0.62±0.38 | 3.06±0.64 | 3.12±1.08 |
| Spleen | 0.63±0.28 | 0.37±0.12 | 0.47±0.22 | 0.27±0.06 | 0.21±0.05 |
| Lung | 2.60±0.44 | 2.23±0.41 | 0.82±0.27 | 1.65±0.56 | 2.01±0.45 |
| Kidney | 136.65±10.01 | 113.43±17.42 | 15.38±1.71a | 69.31±7.55b | 112.04±13.03 |
| Bone | 0.83±0.88 | 0.94±1.21 | 1.24±0.90 | 0.93±0.74 | 0.42±0.33 |
| Muscle | 2.81±0.84 | 2.40±1.35 | 1.23±0.79 | 2.64±0.15 | 2.73±0.94 |
| Stomach | 2.94±0.29 | 1.62±0.64 | 1.04±0.35 | 1.93±0.29 | 1.30±0.41 |
| Intestine | 1.79±0.38 | 1.71±0.22 | 1.42±0.17 | 1.29±0.25 | 1.06±0.62 |
| Tumor | 9.77±1.54 | 9.68±1.24 | 2.00±0.97a | 12.97±1.07 | 11.93±1.98 |
| Blood | 0.65±0.09 | 0.25±0.05 | 0.62±0.19 | 0.59±0.47 | 0.13±0.06 |
| Ratio of tumor/muscle | 3.47 | 4.04 | 4.91 | 4.38 | |
| Ratio of tumor/blood | 14.99 | 38.51 | 21.98 | 91.17 | |
| Ratio of tumor/kidney | 0.07 | 0.09 | 0.19 | 0.11 | |
| Ratio of tumor/liver | 2.62 | 2.50 | 4.24 | 3.82 | |
Table 4 Biodistribution of 99mTc(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS) in KB tumor-bearing mice(n=5)
| Sample | Biodistribution/(%ID·g-1) | ||||
|---|---|---|---|---|---|
| 1 h | 2 h | 2 h(Blockade) | 2 h(PMX) | 4 h | |
| Heart | 3.06±0.90 | 3.45±1.04 | 0.44±0.26 | 2.52±0.48 | 2.89±0.68 |
| Liver | 3.73±0.55 | 3.87±1.57 | 0.62±0.38 | 3.06±0.64 | 3.12±1.08 |
| Spleen | 0.63±0.28 | 0.37±0.12 | 0.47±0.22 | 0.27±0.06 | 0.21±0.05 |
| Lung | 2.60±0.44 | 2.23±0.41 | 0.82±0.27 | 1.65±0.56 | 2.01±0.45 |
| Kidney | 136.65±10.01 | 113.43±17.42 | 15.38±1.71a | 69.31±7.55b | 112.04±13.03 |
| Bone | 0.83±0.88 | 0.94±1.21 | 1.24±0.90 | 0.93±0.74 | 0.42±0.33 |
| Muscle | 2.81±0.84 | 2.40±1.35 | 1.23±0.79 | 2.64±0.15 | 2.73±0.94 |
| Stomach | 2.94±0.29 | 1.62±0.64 | 1.04±0.35 | 1.93±0.29 | 1.30±0.41 |
| Intestine | 1.79±0.38 | 1.71±0.22 | 1.42±0.17 | 1.29±0.25 | 1.06±0.62 |
| Tumor | 9.77±1.54 | 9.68±1.24 | 2.00±0.97a | 12.97±1.07 | 11.93±1.98 |
| Blood | 0.65±0.09 | 0.25±0.05 | 0.62±0.19 | 0.59±0.47 | 0.13±0.06 |
| Ratio of tumor/muscle | 3.47 | 4.04 | 4.91 | 4.38 | |
| Ratio of tumor/blood | 14.99 | 38.51 | 21.98 | 91.17 | |
| Ratio of tumor/kidney | 0.07 | 0.09 | 0.19 | 0.11 | |
| Ratio of tumor/liver | 2.62 | 2.50 | 4.24 | 3.82 | |
| Complex | Biodistribution/(%ID·g-1) | |||
|---|---|---|---|---|
| Tumor | Tumor/Muscle | Tumor/Blood | Tumor/Liver | |
| 99mTc(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS) | 11.93±1.98 | 4.38 | 91.17 | 3.82 |
| 99mTc-EC20 | 12.26±1.05 | — | 59.56 | 3.40 |
| 111In-DTPA-folate(γ) | 6.8± 1.2 | 2.5 | 106 | 3.3 |
Table 5 Comparison of biodistribution data between 99mTc(HYNIC-Gly-Gly-lys-Pteroyl) and other FR imaging agents in KB tumor-bearing mice at 4 h post-injection
| Complex | Biodistribution/(%ID·g-1) | |||
|---|---|---|---|---|
| Tumor | Tumor/Muscle | Tumor/Blood | Tumor/Liver | |
| 99mTc(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS) | 11.93±1.98 | 4.38 | 91.17 | 3.82 |
| 99mTc-EC20 | 12.26±1.05 | — | 59.56 | 3.40 |
| 111In-DTPA-folate(γ) | 6.8± 1.2 | 2.5 | 106 | 3.3 |
Fig.4 Whole-body, coronal and transaxial images 99mTc(HYNIC-penta-lys-Pteroyl)(Tricine/TPPTS)(A―D) and 99mTc(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS)(E―H) in the athymic nude mice bearing KB tumors(female, 18—20 g) at 120 min p.i.; tumors(T) and kidneys(K) were highlighted with arrows on the images. The uptakes of radiotracer in FR-positive tumors were significantly blocked by co-injection of excess folic acid(A and E).
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