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Hybrid Tracers Based on Cyanine Backbones Targeting Prostate-Specific Membrane Antigen: Tuning Pharmacokinetic Properties and Exploring Dye–Protein Interaction
The Journal of Nuclear Medicine ( IF 9.3 ) Pub Date : 2020-02-01 , DOI: 10.2967/jnumed.119.233064
Albertus W. Hensbergen , Tessa Buckle , Danny M. van Willigen , Margret Schottelius , Mick M. Welling , Felicia A. van der Wijk , Tobias Maurer , Henk G. van der Poel , Gabri van der Pluijm , Wytske M. van Weerden , Hans-Jürgen Wester , Fijs W.B. van Leeuwen

Prostate cancer surgery is currently being revolutionized by the use of prostate-specific membrane antigen (PSMA)–targeted radiotracers, for example, 99mTc-labeled PSMA tracer analogs for radioguided surgery. The purpose of this study was to develop a second-generation 99mTc-labeled PSMA-targeted tracer incorporating a fluorescent dye. Methods: Several PSMA-targeted hybrid tracers were synthesized: glutamic acid-urea-lysine (EuK)-Cy5-mas3, EuK-(SO3)Cy5-mas3, EuK-Cy5(SO3)-mas3, EuK-(Ar)Cy5-mas3, and EuK-Cy5(Ar)-mas3; the Cy5 dye acts as a functional backbone between the EuK targeting vector and the 2-mercaptoacetyl-seryl-seryl-seryl (mas3) chelate to study the dye’s interaction with PSMA’s amphipathic entrance funnel. The compounds were evaluated for their photophysical and chemical properties and PSMA affinity. After radiolabeling with 99mTc, we performed in vivo SPECT imaging, biodistribution, and fluorescence imaging on BALB/c nude mice with orthotopically transplanted PC346C tumors. Results: The dye composition influenced the photophysical properties (brightness range 0.3–1.5 × 104 M−1 × cm−1), plasma protein interactions (range 85.0% ± 2.3%–90.7% ± 1.3% bound to serum, range 76% ± 0%–89% ± 6% stability in serum), PSMA affinity (half-maximal inhibitory concentration [IC50] range 19.2 ± 5.8–175.3 ± 61.1 nM) and in vivo characteristics (tumor-to-prostate and tumor-to-muscle ratios range 0.02 ± 0.00–154.73 ± 28.48 and 0.46 ± 0.28–5,157.50 ± 949.17, respectively; renal, splenic, and salivary retention). Even though all tracer analogs allowed tumor identification with SPECT and fluorescence imaging, 99mTc-EuK-(SO3)Cy5-mas3 had the most promising properties (e.g., half-maximal inhibitory concentration, 19.2 ± 5.8, tumor-to-muscle ratio, 5,157.50 ± 949.17). Conclusion: Our findings demonstrate the intrinsic integration of a fluorophore in the pharmacophore in PSMA-targeted small-molecule tracers. In this design, having 1 sulfonate on the indole moiety adjacent to EuK (99mTc-EuK-(SO3)Cy5-mas3) yielded the most promising tracer candidate for imaging of PSMA.



中文翻译:

基于花青主链的针对前列腺特异性膜抗原的杂交示踪剂:调节药代动力学特性和探索染料-蛋白质相互作用

前列腺癌手术目前正在通过使用靶向前列腺特异性膜抗原(PSMA)的放射性示踪剂(例如99m Tc标记的PSMA示踪剂类似物)用于放射性引导手术而发生革命性变化。这项研究的目的是开发结合了荧光染料的第二代99m Tc标记的PSMA靶向示踪剂。方法:合成了几种靶向PSMA的杂交示踪剂:谷氨酸-尿素-赖氨酸(EuK)-Cy5-mas 3,EuK-(SO 3)Cy5-mas 3,EuK-Cy5(SO 3)-mas 3,EuK- (Ar)Cy5-mas 3和EuK-Cy5(Ar)-mas 3; Cy5染料充当EuK靶向载体和2-巯基乙酰基-丝氨酰-丝氨酰-丝氨酰(mas 3)螯合物之间的功能骨架,以研究该染料与PSMA的两亲性入口漏斗的相互作用。对化合物的光物理和化学性质以及PSMA亲和力进行了评估。在用99m Tc进行放射性标记后,我们对原位移植PC346C肿瘤的BALB / c裸鼠进行了体内SPECT成像,生物分布和荧光成像。结果:染料组成影响光物理性质(亮度范围0.3–1.5×10 4 M -1 ×cm -1),血浆蛋白相互作用(结合血清的范围为85.0%±2.3%–90.7%±1.3%,结合血清的范围为76%±0%–89%±6%),PSMA亲和力(半最大抑制浓度[IC 50 ]范围为19.2±5.8–175.3±61.1 nM)和体内特征(肿瘤与前列腺和肿瘤与肌肉的比例分别为0.02±0.00–154.73±28.48和0.46±0.28–5,157.50±949.17);肾脏,脾脏和唾液retention留)。即使所有示踪剂类似物都可以通过SPECT和荧光成像进行肿瘤鉴定,但99m Tc-EuK-(SO 3)Cy5-mas 3具有最有希望的特性(例如,最大抑制浓度的一半,19.2±5.8,肿瘤对肌肉比,5,157.50±949.17)。结论:我们的发现证明了在PSMA靶向的小分子示踪剂中,荧光团在药效团中的内在整合。在此设计中,在与EuK相邻的吲哚部分上有1个磺酸盐(99m Tc-EuK-(SO 3)Cy5-mas 3)产生了最有希望的PSMA示踪剂候选。

更新日期:2020-02-03
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