Hybrid Tracers Based on Cyanine Backbones Targeting Prostate-Specific Membrane Antigen: Tuning Pharmacokinetic Properties and Exploring Dye-Protein Interaction
| Autor: | Margret Schottelius, Henk G. van der Poel, Gabri van der Pluijm, Mick M. Welling, Albertus W. Hensbergen, Wytske M. van Weerden, Hans-Jürgen Wester, Fijs W. B. van Leeuwen, Felicia A. van der Wijk, Danny M. van Willigen, Tobias Maurer, Tessa Buckle |
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| Přispěvatelé: | Urology |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Glutamate Carboxypeptidase II
Biodistribution Fluorescence-lifetime imaging microscopy Fluorophore image-guided surgery 01 natural sciences Mice 03 medical and health sciences chemistry.chemical_compound prostate-specific membrane antigen 0302 clinical medicine In vivo Cell Line Tumor Spect imaging Animals Humans Tissue Distribution Radiology Nuclear Medicine and imaging Radioactive Tracers Cyanine Coloring Agents IC50 Tomography Emission-Computed Single-Photon 010405 organic chemistry Carbocyanines cyanine prostate cancer Fluorescence 0104 chemical sciences Cell Transformation Neoplastic chemistry 030220 oncology & carcinogenesis Antigens Surface Biophysics hybrid tracers |
| Zdroj: | Journal of Nuclear Medicine, 61(2), 234-241. Society of Nuclear Medicine and Molecular Imaging Journal of Nuclear Medicine, 61(2), 234-241. SOC NUCLEAR MEDICINE INC |
| ISSN: | 2159-662X 0161-5505 |
| DOI: | 10.2967/jnumed.119.233064 |
| Popis: | Prostate cancer surgery is currently being revolutionized by the use of prostate-specific membrane antigen (PSMA)-targeted radiotracers, for example, (99)mTc-labeled PSMA tracer analogs for radioguided surgery. The purpose of this study was to develop a second-generation (99)mTc-labeled PSMA-targeted tracer incorporating a fluorescent dye. Methods: Several PSMA-targeted hybrid tracers were synthesized: glutamic acid- urea-lysine (EuK)-Cy5-mas(3), EuK-(SO3)Cy5-mas(3), EuK-Cy5(SO3)-mas(3), EuK-(Ar)Cy5-mas(3), and EuK-Cy5(Ar)-mas(3); the Cy5 dye acts as a functional backbone between the EuK targeting vector and the 2-mercaptoacetyl-seryl-seryl-seryl (mas(3)) 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 (99)mTc, 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 x 10(4) M-1 x 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 (tumorto-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, (99)mTc-EuK(SO3)Cy5-mas(3) 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 smallmolecule tracers. In this design, having 1 sulfonate on the indole moiety adjacent to EuK ((99)mTc-EuK-(SO3)Cy5-mas(3)) yielded the most promising tracer candidate for imaging of PSMA. |
| Databáze: | OpenAIRE |
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