A conjugated bis-benzimidazole chromophore is predicted to show absorptions in the near-infrared (NIR) region of the electromagnetic spectrum. However, there are no reports to-date of any NIR absorbing and emitting dyes that are based on a bis-benzimidazole structural backbone. This thesis reports recent advancements in the discovery and study of this new class of dyes. Following literature procedures, the syntheses of bis(benzimidazolyl)methane compounds are successful. An unexpected product isolated during the attempted oxidation of a bis(benzimidazolyl)methane compound using p-chloranil showed intense absorption in the NIR (λmax = 712 nm, ε = 14600 L·mol-1·cm-1), solubilities in polar solvents like methanol and water, and electrochemical activities. X-ray crystallography, mass spectrometry, and NMR spectroscopy confirmed the connectivity and structure of the product to contain a combination of quinone and benzimidazole moieties, which later revealed to be the core chromophore by computational studies. This unprecedented combination of moieties gave a chromophore that is predicted to absorb in the far-red even without substitution. Attempts to synthesize boron-based bis-imidazole dyes with N-methylation shed light on the feasibility of the design of such moiety. Considering the additional functionality that could be accessed through the methylation of the labile benzimidazole nitrogen atoms, N-methylated bis(benzimidazolyl)methane precursors were successfully synthesized and fully characterized. Attempts of the boron coordination showed promising signs, as the 1H, 11B, and 19F NMR spectra showed solid evidence of the successful isolation of the boron chelate. Computational studies of methyl, phenyl, and triazole-substituted boron chelate derivatives projected absorptions in the NIR region. Intense transitions are found to be based on frontier molecular orbitals and differ significantly among the derivatives, predicting substantial tunability of this type of dyes. / Graduate / 2022-02-18

To address the paucity of available molecularly targeted photoacoustic imaging probes (PIPs) and to generate meaningful data to support the ongoing effort to refine diagnostic photoacoustic imaging (PAI) applications, the work presented here focuses on the design, synthesis, and evaluation of novel PIPs. To this end, various light-absorbing small molecule dyes, targeting strategies, and disease-targeting molecules were evaluated. First, a near-infrared photoacoustic probe was used to image bone in vivo through active and bioorthogonal pre-targeting strategies by utilizing a coupling between a tetrazine-derived cyanine dye and a trans-cyclooctene-modified bisphosphonate. In vitro hydroxyapatite binding and in vivo bone imaging studies showed significant localization of the agent to the target using both active and pre-targeting strategies. The tetrazine-dye building block was then used to create a first-generation bacteria-targeting PIP, using a trans-cyclooctene-modified Zinc (II)-dipicolylamine (ZnDPA). The PIP demonstrated poor aqueous solubility and overlapping photoacoustic (PA) signal with deoxyhemoglobin. Therefore, a commercially available ZnDPA-derived fluorophore, PSVue794, was then repurposed for use as a PIP. PSVue794 demonstrated the ability to differentiate between bacterial infection, sterile inflammation, and healthy tissue in a mouse model, via PA imaging, which prompted its use in a series of proof-of-concept studies towards the generation of a model of implant infection. The feasibility of detecting the PIP in the presence of a PA signal-emitting metallic implant, which was deemed a significant hurdle due to the intensity of the PA signal of the metal, was verified. Although the work requires some follow-up evaluations to demonstrate the practical use of the model, ZnDPA-based PIPs have remained promising candidates for PAI of bacterial infection. Finally, a novel general-purpose dye was designed to possess properties ideal for in vivo PAI. To evaluate the modifications made, the general-purpose dye was conjugated with ZnDPA, and was tested alongside the non-targeted counterpart and PSVue794. Through the studies conducted, it was evident that the rationale that contributed to the design of the general-purpose dye did lead to highly soluble PIP with promising PA properties, however, the PIP did not demonstrate target-specificity, in vivo. Therefore, investigations using the non-targeted PIP with higher affinity targeting vectors for PA-compatible diseases, such as surgical-site/implant infections and prostate cancer, is warranted. / Thesis / Doctor of Philosophy (PhD) / The work conducted within this thesis aims to outline the process of developing photoacoustic diagnostic agents for the detection of various diseases, including bone disease and bacterial infection. To this end, various small molecule, near-infrared absorbing dyes, disease-targeting molecules, and assembly methods were selected to generate several diagnostic agents. To demonstrate their utility, the diagnostic agents were each evaluated in a series of studies designed to assess their ability to generate detectable photoacoustic signal, interact specifically with disease-markers, and localize the sites of disease in living systems. Significant attention was placed on comprehensively evaluating the diagnostic agents through the development of methodology and generating a standard procedure for photoacoustic data production and reporting, which was practiced throughout the work.

Les colorants organiques du proche infrarouge présentent un intérêt majeur dans différent secteurs technologiques. Les travaux présentés dans cette thèse portent sur le développement de ce type de chromophores à partir d’unités quinones possédant une conjugaison électronique particulière : les 2,5-diamino-1,4-benzoquinone-diimines (DABQDI). De nouvelles DABQDI ont pu être synthétisées et leur utilisation comme ligand a notamment permis d’obtenir des complexes absorbant du domaine visible jusqu’à celui du proche infrarouge. Ces unités DABQDI ont également pu être incorporées au sein de macrocycles, analogues de porphyrines, appelés azacalixphyrines, capables d’absorber la lumière jusqu’à 1000 nm. / Near infrared dyes play a significant role in various technological sectors. The present PhD manuscript concerns the development of such chromophores built on quinone units that have a particular electronic delocalization: the 2,5-diamino-1,4-benzoquinone-diimines (DABQDI). New DABQDI have been synthesized and their use as ligand can provide complexes absorbing from the visible to the near infrared domain. DABQDI units were also incorporated in macrocycles, analogous of porphyrins, called azacalixphyrins, able to absorb light up to 1000 nm.

L’objectif de cette thèse consistait à développer des colorants de la famille des polyméthines absorbant dans le proche infrarouge et présentant des propriétés d’optique non-linéaire (ONL) prononcées. De nouveaux chromophores ont été préparés et leurs propriétés spectroscopiques ont été systématiquement étudiées afin d’établir des relations structures-propriétés. Cette stratégie a permis l’identification des facteurs permettant d’exalter la réponse ONL des polyméthines et de prédire leur comportement face à de subtiles modifications structurales. Trois familles de colorants ont été préparées : des monométhines aza-dipyrrométhènes de bore, des heptaméthines symétriques ainsi que des heptaméthines dissymétriques.Dans un premier temps, des aza-bodipys possédant des groupements donneurs périphériques sont synthétisés. Une étude spectroscopique approfondie permet d’identifier les structures présentant une absorption à deux photons importante en vue d’applications en limitation optique aux longueurs d’onde des télécommunications (1500 nm). Le chapitre suivant a pour but de rationaliser les équilibres de la limite cyanine. L’étude de la substitution centrale de nombreux dérivés heptaméthines a permis de moduler leurs propriétés optiques sur une large gamme spectrale et de mettre en évidence une nouvelle structure électronique limite de type bis-dipôle. Parmi cette famille de colorants, des dérivés keto-heptaméthines ont été utilisées en imagerie biologique (cellules et cerveau) par microscopie non-linéaire. Enfin, l’élaboration de structures heptaméthines dissymétriques originales est détaillée dans le dernier chapitre. Ces chromophores ont révélé des propriétés ONL du second ordre idéales pour des applications en modulation électro-optique. / The aim of this thesis consisted in developing dyes from the polymethine family absorbing in the near-infrared (NIR) region and featuring pronounced nonlinear optical (NLO) properties. Several new chromophores have been prepared and their spectroscopic properties have been systematically investigated in order to establish structure-properties relationships. This strategy has permitted the identification of the factors that enhance the NLO response of polymethines and allowed the prediction of their optical behaviour depending on subtle structural modifications. Three families of dyes have been prepared and investigated: boron aza-dipyrro-monomethines (aza-bodipys), symmetrical heptamethines and unsymmetrical heptamethines.In a first time, aza-bodipys possessing electro-donating peripherical substituants has been synthesized. A detailed spectroscopic study allow the identification of structures that present a high two-photon absorption (TPA), towards optical limiting applications at telecommunication wavelengths (1500 nm). The next chapter rationalizes the equilibrium surrounding the cyanine limit. The study of the central substitution of several heptamethines derivatives permitted the fine tuning of their optical properties upon a large spectral region and evidenced a new bis-dipolar electronic structure. Within this dye family, keto heptamethine derivatives has been tested in bio-imaging experiments (living cells and brain) using non-linear microscopy. Finally, the elaboration of original unsymmetrical heptamethines is detailed in the last chapter. These chromophores revealed ideal second order NLO properties for applications in electro-optic modulation.