Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
Pharmazeutische Radiochemie, Technische Universität München, Garching, Germany.
J Nucl Med. 2020 Feb;61(2):234-241. doi: 10.2967/jnumed.119.233064. Epub 2019 Sep 3.
Prostate cancer surgery is currently being revolutionized by the use of prostate-specific membrane antigen (PSMA)-targeted radiotracers, for example, Tc-labeled PSMA tracer analogs for radioguided surgery. The purpose of this study was to develop a second-generation Tc-labeled PSMA-targeted tracer incorporating a fluorescent dye. Several PSMA-targeted hybrid tracers were synthesized: glutamic acid-urea-lysine (EuK)-Cy5-mas, EuK-(SO)Cy5-mas, EuK-Cy5(SO)-mas, EuK-(Ar)Cy5-mas, and EuK-Cy5(Ar)-mas; the Cy5 dye acts as a functional backbone between the EuK targeting vector and the 2-mercaptoacetyl-seryl-seryl-seryl (mas) 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 Tc, we performed in vivo SPECT imaging, biodistribution, and fluorescence imaging on BALB/c nude mice with orthotopically transplanted PC346C tumors. The dye composition influenced the photophysical properties (brightness range 0.3-1.5 × 10 M × cm), 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 [IC] 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, Tc-EuK-(SO)Cy5-mas had the most promising properties (e.g., half-maximal inhibitory concentration, 19.2 ± 5.8, tumor-to-muscle ratio, 5,157.50 ± 949.17). 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 (Tc-EuK-(SO)Cy5-mas) yielded the most promising tracer candidate for imaging of PSMA.
前列腺癌手术目前正在发生革命性的变化，例如使用前列腺特异性膜抗原（PSMA）靶向放射性示踪剂，例如 Tc 标记的 PSMA 示踪剂类似物用于放射性引导手术。本研究的目的是开发一种包含荧光染料的第二代 Tc 标记的 PSMA 靶向示踪剂。合成了几种 PSMA 靶向杂交示踪剂：谷氨酸-脲-赖氨酸（EuK）-Cy5-mas、EuK-（SO）Cy5-mas、EuK-Cy5（SO）-mas、EuK-（Ar）Cy5-mas 和 EuK-Cy5（Ar）-mas；Cy5 染料作为 EuK 靶向载体与 2-巯基乙酰基-丝氨酰-丝氨酰-丝氨酰（mas）螯合物之间的功能骨架，以研究染料与 PSMA 两亲入口漏斗的相互作用。评估了这些化合物的光物理和化学性质以及 PSMA 亲和力。用 Tc 标记后，我们在原位移植 PC346C 肿瘤的 BALB/c 裸鼠上进行了 SPECT 成像、生物分布和荧光成像。染料组成影响光物理性质（亮度范围 0.3-1.5×10 M×cm）、血浆蛋白相互作用（结合血清的范围为 85.0%±2.3%-90.7%±1.3%，在血清中稳定的范围为 76%±0%-89%±6%）、PSMA 亲和力（半最大抑制浓度 [IC] 范围 19.2±5.8-175.3±61.1 nM）和体内特性（肿瘤-前列腺和肿瘤-肌肉比范围为 0.02±0.00-154.73±28.48 和 0.46±0.28-5,157.50±949.17；肾、脾和唾液保留）。尽管所有示踪剂类似物都允许通过 SPECT 和荧光成像识别肿瘤，但 Tc-EuK-（SO）Cy5-mas 具有最有前途的特性（例如，半最大抑制浓度为 19.2±5.8，肿瘤-肌肉比为 5,157.50±949.17）。我们的研究结果表明，荧光团在 PSMA 靶向小分子示踪剂的药效团中固有地整合。在这种设计中，在与 EuK 相邻的吲哚部分上具有 1 个磺酸盐（Tc-EuK-（SO）Cy5-mas）产生了最有前途的 PSMA 成像示踪剂候选物。
