Hybrid Tracers Based on Cyanine Backbones Targeting Prostate-Specific Membrane Antigen: Tuning Pharmacokinetic Properties and Exploring Dye–Protein Interaction

作者：A. W. Hensbergen, T. Buckle, D. V. van Willigen, M. Schottelius, M. Welling, Felicia A. van der Wijk, T. Maurer, H. G. van der Poel, G. van der Pluijm, W. V. van Weerden, H. Wester, F. V. van Leeuwen · 发表于：Journal of Nuclear Medicine · 年份：2020 · DOI：10.2967/jnumed.119.233064 · 被引用次数：52 · 研究领域：Medicine、Chemistry

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, spleni...