Synthesis and biological evaluation of low molecular weight fluorescent imaging agents for the prostate-specific membrane antigen.

Abstract

Targeted near-infrared (NIR) optical imaging can be used in vivo to detect specific tissues, including malignant cells. A series of NIR fluorescent ligands targeting the prostate-specific membrane antigen (PSMA) was synthesized and each compound was tested for its ability to image PSMA+ tissues in experimental models of prostate cancer. The agents were prepared by conjugating commercially available active esters of NIR dyes, including IRDye800CW, IRDye800RS, Cy5.5, Cy7, or a derivative of indocyanine green (ICG) to the terminal amine group of (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)pentanedioic acid 1, (14S,18S)-1-amino-8,16-dioxo-3,6-dioxa-9,15,17-triazaicosane-14,18,20-tricarboxylic acid 2 and (3S,7S)-26-amino-5,13,20-trioxo-4,6,12,21-tetraazahexacosane-1,3,7,22-tetracarboxylic acid 3. The K(i) values for the dye-inhibitor conjugates ranged from 1 to 700 pM. All compounds proved capable of imaging PSMA+ tumors selectively to varying degrees depending on the choice of fluorophore and linker. The highest tumor uptake was observed with IRDye800CW employing a poly(ethylene glycol) or lysine-suberate linker, as in 800CW-2 and 800CW-3, while the highest tumor to nontarget tissue ratios were obtained for Cy7 with these same linkers, as in Cy7-2 and Cy7-3. Compounds 2 and 3 provide useful scaffolds for targeting of PSMA+ tissues in vivo and should be useful for preparing NIR dye conjugates designed specifically for clinical intraoperative optical imaging devices.

• Authors: Ying Chen, Mrudula Pullambhatla, Sangeeta R Banerjee, Youngjoo Byun, Marigo Stathis, Camilo Rojas, Barbara S Slusher, Ronnie C Mease, Martin G Pomper
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 23 Issue 12 Pg. 2377-85 (Dec 19 2012) ISSN: 1520-4812 [Electronic] United States
• PMID: 23157641 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carboxylic Acids
• Fluorescent Dyes
• Membrane Glycoproteins
• Polyethylene Glycols
• Glutamate Carboxypeptidase II
• PSMA protein, mouse
• Lysine

Topics

• Animals
• Carboxylic Acids (chemistry)
• Disease Models, Animal
• Fluorescent Dyes (chemical synthesis, pharmacokinetics, pharmacology)
• Glutamate Carboxypeptidase II (analysis, metabolism)
• Humans
• Kinetics
• Lysine (analogs & derivatives)
• Male
• Membrane Glycoproteins (analysis, metabolism)
• Mice
• Mice, Nude
• Molecular Imaging (instrumentation, methods)
• Molecular Weight
• Polyethylene Glycols (chemistry)
• Prostate (drug effects, metabolism, pathology)
• Prostatic Neoplasms (metabolism, pathology)
• Spectroscopy, Near-Infrared (instrumentation, methods)