title: cGMP-Compatible preparative scale synthesis of near-infrared fluorophores.
abstract: Image-guided surgery using optical imaging requires the availability of large quantities of clinical-grade fluorophores. We describe the cGMP-compatible synthesis of the zwitterionic heptamethine indocyanine near-infrared fluorophore ZW800-1 at the 10 g scale (~1000 patient doses) using facile and efficient solvent purification, and without the need for column chromatography. ZW800-1 has >90% yield at the final step and >99% purity as measured by fluorescence and evaporative light scatter detection. We describe an analytical framework for qualifying impurities, as well as a detailed analysis of counterion identities. Finally, we report the unique in vivo properties of ZW800-1 in large animals approaching the size of humans, thus laying the foundation for rapid clinical translation of these methods.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Hoon
authors.initials: H
authors.lastname: Hyun
authors.forename: Mark W
authors.initials: MW
authors.lastname: Bordo
authors.forename: Khaled
authors.initials: K
authors.lastname: Nasr
authors.forename: Dina
authors.initials: D
authors.lastname: Feith
authors.forename: Jeong Heon
authors.initials: JH
authors.lastname: Lee
authors.forename: Soon Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Ashitate
authors.forename: Lorissa A
authors.initials: LA
authors.lastname: Moffitt
authors.forename: Mireille
authors.initials: M
authors.lastname: Rosenberg
authors.forename: Maged
authors.initials: M
authors.lastname: Henary
authors.forename: Hak Soo
authors.initials: HS
authors.lastname: Choi
authors.forename: John V
authors.initials: JV
authors.lastname: Frangioni
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000737:chemistry*; D005260:Female; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019265:Spectroscopy, Near-Infrared; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013552:Swine
chemical_list: D005456:Fluorescent Dyes; D000644:Quaternary Ammonium Compounds; D013451:Sulfonic Acids; C562069:ZW800-1 compound; D006152:Cyclic GMP