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

Bioconjug Chem. 2012 Dec 19;23(12):2377-85. doi: 10.1021/bc3003919. Epub 2012 Dec 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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