99mTc标记蝶呤-赖氨酸衍生物的制备及生物性能评价

doi:10.7503/cjcu20150388

摘要/Abstract

摘要：

基于蝶呤-赖氨酸分子结构, 设计合成了2种 ^99mTc标记配合物 ^99mTc(HYNIC-penta-lys-Pteroyl)-(Tricine/TPPTS)和 ^99mTc(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS), 并对其生物性能进行了初步评价. 研究结果表明, 2种配合物在叶酸受体高表达的人口腔表皮样癌(KB)细胞中均有很高的摄取和滞留. 给药1 h后, ^99mTc(HYNIC-penta-lys-Pteroyl)(Tricine/TPPTS)和 ^99mTc(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS)在荷KB肿瘤裸鼠体内的肿瘤摄取率分别为(8.55±2.78) %ID/g和(9.77±1.54) %ID/g. 荷KB肿瘤裸鼠的小动物SPECT/CT显像研究结果表明, 上述2种标记配合物在给药2 h后, 其肿瘤部位均清晰可见, 有望作为新型的叶酸受体靶向肿瘤分子探针.

关键词: 99mTc, 叶酸受体, 蝶呤-赖氨酸衍生物, 肿瘤显像

Abstract:

Two ^99mTc labeled complexes, ^99mTc(HYNIC-penta-lys-Pteroyl)(Tricine/TPPTS) and ^99mTc-(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS), were prepared based on the structure of Pteroyl-lys. Both two complexes exhibited high receptor specific binding and extended retention in KB human epidermoid carcinoma cells. The tumor uptake values of ^99mTc(HYNIC-penta-lys-Pteroyl)(Tricine/TPPTS) and ^99mTc(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS) were (8.55±2.78)%ID/g and (9.77±1.54)%ID/g at 1 h postinjection, respectively. Flank KB tumors were clearly visualized with ^99mTc(HYNIC-penta-lys-Pteroyl)(Tricine/TPPTS) and ^99mTc(HYNIC-Gly-Gly-lys-Pteroyl)(Tricine/TPPTS) by Micro-SPECT/CT images at 2 h postinjection. High receptor-specific tumor uptakes coupled with fast non-target tissues clearance demonstrated the feasibility of using ^99mTc-labeled Pteroyl-lys derivatives as novel imaging probes for FR-positive tumors detection.

Key words: 99mTc, Folate receptor, Pteroyl-lys derivative, Tumor imaging

TrendMD:

于倩, 何颖芳, 陈媛, 杨文江, 张春, 陆洁. ^99mTc标记蝶呤-赖氨酸衍生物的制备及生物性能评价. 高等学校化学学报, 2015, 36(12): 2446.

YU Qian, HE Yingfang, CHEN Yuan, YANG Wenjiang, ZHANG Chun, LU Jie. Preparation and Biological Evaluation of ^99mTc-labeled Pteroyl-lys Derivatives^†. Chem. J. Chinese Universities, 2015, 36(12): 2446.

图/表 10

参考文献 21

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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.	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

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

Sample	Biodistribution/(%ID·g^-1)
Sample	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±0.69^a	44.11±6.89^b	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±0.49^a	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