A chemically stable fluorescent marker of the ureter

Abstract

Surgical methods guided by exogenous fluorescent markers have the potential to define tissue types in real time. Small molecule dyes with efficient and selective renal clearance could enable visualization of the ureter during surgical procedures involving the abdomen and pelvis. These studies report the design and synthesis of a water soluble, net neutral C4'-O-alkyl heptamethine cyanine, Ureter-Label (UL)-766, with excellent properties for ureter visualization. This compound is accessed through a concise synthetic sequence involving an N- to O-transposition reaction that provides other inaccessible C4'-O-alkyl heptamethine cyanines. Unlike molecules containing a C4'-O-aryl substituent, which have also been used for ureter visualization, UL-766 is not reactive towards glutathione and the cellular proteome. In addition, rat models of abdominal surgery reveal that UL-766 undergoes efficient and nearly exclusive renal clearance in vivo. In total, this molecule represents a promising candidate for visualizing the ureter during a variety of surgical interventions.

Site-Specific Labeling of Proteins with Near-IR Heptamethine Cyanine Dyes

“…The corresponding amino-acid-substituted Cy-7 dyes were indeed formed ( Scheme 1 ); these were isolated, characterized (see supplementary materials for NMR and mass spectrometry), and later used as standards for comparison of high-performance liquid chromatography (HPLC) retention times. Serine was excluded from these experiments because alcohol hydroxyl groups are known to not substitute the meso -Cl without complications [ 17 , 18 , 19 , 20 ].…”

Sterically Shielded Heptamethine Cyanine Dyes for Bioconjugation and High Performance Near‐Infrared Fluorescence Imaging

“…[6c, 9] The second structural improvement is to replace the dyesl abile meso CÀOa ryl bond with am ore stable covalent linkage.A recent advance developed by Schnermann and co-workers employed amore robust meso CÀOalkyl bond, [6c, 8a] and one example of this fluorochrome is UL766, which exhibits excellent chemical stability and very favorable pharmacokinetics due to its charge balanced structure. [10] However,t he heptamethine polyene within UL766, (and its close structural analogues) is quite electron rich which means relatively high fluorochrome reactivity with singlet oxygen, and thus susceptibility to photobleaching. [8a] Another way to replace the reactive meso C À Oaryl bond in ZW800-1 is to employ amuch more stable C À Clinkage as exemplified by 756z with its mesoaryl substituent.…”

Site-Specific Labeling of Proteins with Near-IR Dyes

“…retention times. Serine was excluded from these experiments because alcohol hydroxyl groups are known to not substitute the meso-Cl without complications[17][18][19][20].N-Acetyl-L-cysteine was the most reactive nucleophile of the five amino acids studied. In the presence of Hünig's base, MHI-148 was completely converted to the thiol-substituted product within an hour at 25 °C in DMF (0.1 M 1:1 dye:Cys-derivative, LC-MS analyses).…”