Shortwave infrared (SWIR, 1000-2000 nm) small molecule fluorophores have found increased use towards in vivo optical imaging applications due to the enhanced penetration of low energy light through tissue and decreased background autofluorescence of endogenous chromophores resulting in a high signal to noise ratio. Polymethine dyes are bright, clinically relevant contrast agents for SWIR detection and have been recently developed to afford real-time multiplexed imaging. Using nude mice models and utilizing already established fluorophores, their applications beyond passive vasculature imaging will be expanded by covalently appending targeting moieties to image biological structures of interest. Functionalized polymethine fluorophores have been traditionally synthesized via nucleophilic substitution using amines, thiols, and phenols. However, the resulting chromophores are chemically unstable, presumably due to their susceptibility for nucleophilic substitution, limiting their use in biological systems. Instead, C-C or C-O-alkyl bonds are desirable because these bonds are stronger and therefore lead to a more stable fluorophore. Moving away from traditional nucleophilic substitution-based chemistries, the targeting moieties are appended via palladium-mediated cross-coupling methods to afford stable C-Caryl, C-Csp2, and until now, unprecedented C-Oalkyl functionalized fluorophores. Mechanistic studies are conducted to confirm the palladium-mediated nature of the C-Oalkyl transformation. The resulting functionalized fluorophores are photophysically characterized and are shown to retain the high brightness and stability particular to polymethine dyes. The palladium functionalized fluorophores are further derivatized to afford three targeted contrast agents to be used in three color imaging in nude mice.

Palladium-catalyzed functionalization of polymethine fluorophores towards SWIR targeted multiplexed imaging

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