title: 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.affiliation: Russell H. Morgan Department of Radiology, Brain Science Institute, Johns Hopkins Medical School, Baltimore, MD 21231, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Mrudula
authors.initials: M
authors.lastname: Pullambhatla
authors.forename: Sangeeta R
authors.initials: SR
authors.lastname: Banerjee
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.forename: Marigo
authors.initials: M
authors.lastname: Stathis
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D004195:Disease Models, Animal; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging / Q000295:instrumentation / Q000379:methods*; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019265:Spectroscopy, Near-Infrared / Q000295:instrumentation / Q000379:methods*
chemical_list: D002264:Carboxylic Acids; D005456:Fluorescent Dyes; D008562:Membrane Glycoproteins; D011092:Polyethylene Glycols; D043425:Glutamate Carboxypeptidase II; C579805:PSMA protein, mouse; D008239:Lysine