Design and Synthesis of Custom Styryl BODIPY Dyes for Bimodal Imaging

Abstract

Innovation towards new agents for combined positron emission tomography/optical imaging is of significance for making advances in patient diagnosis. As of recent, boron-dipyrromethene (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene, BODIPY) dyes have shown promise as bimodal imaging agents serving as a fluorescent tag with capability to act as a fluorine-18 radiotracer. However, due the sensitivity of these molecules their chemical transformations are poorly understood. In this thesis, I address the synthetic challenge of near-infrared, “clickable” BODIPY dyes with complex functionality in order to identify reliable syntheses. Early investigation was concentrated on understanding the intricacies of BODIPY synthesis; in particular, the low yielding incorporation of boron difluoride. Conventional one-pot procedures were revised, and it was found that isolating the dipyrromethene scaffold followed by boron complexation improved the yield overall. In addition, aqueous work up procedures were modified to avoid the decomplexation of boron difluoride from the BODIPY product by vacuum-assisted removal of excess boron trifluoride. Robust synthetic procedures were established to afford the azido- functionalized BODIPY, which is valuable for tagging novel BODIPY dyes to disease-targeting vectors using “Click Chemistry”. The latter of the thesis focused on improving the water-solubility of the conjugated BODIPY dyes by addition of ionizable groups which can also partake in hydrogen bonding, making them suitable for biological application. It was found that the BODIPY molecule could not withstand ester hydrolysis conditions needed to produce diacid BODIPY derivatives. Alternatively, a Knoevenagel-like condensation provided two near-infrared BODIPY dyes, one bearing dihydroxy (phenolic) functionality demonstrating partial water-solubility. The dyes were characterized as long wavelength dyes to compliment future Price group studies.