Search

Tricarbocyanine dyes have become popular tools in life sciences and medicine. Their near-infrared (NIR) fluorescence makes them ideal agents for imaging of thick specimens or in vivoimaging, e.g., in fluorescence-guided surgery. Among other types of cyanine dyes, meso-Cl tricarbocyanine dyes have received a surge of interest, as it emerged that their high reactivity makes them inherently tumor-targeting. As such, significant research efforts have focused on conjugating these to functional moieties. However, the syntheses generally suffer from low yields. Hereby, we report on the reaction of meso-Cl dyes with a small selection of coupling reagents to give the corresponding keto-polymethines, potentially explaining low yields and the prevalence of monofunctionalized cyanine conjugates in the current state of the art of functional near-infrared dyes. We present the synthesis and isolation of the first keto-polymethine-based conjugate and present preliminary investigation in the prostate cancer cell lines PC3 and DU145 by confocal microscopy and discuss changes to optical properties in biological media.

Over the past decade, porphyrin derivatives have emerged as invaluable synthetic building blocks and theranostic kits for the delivery of cellular fluorescence imaging and photodynamic therapy. Tetraphenylporphyrin (TPP), its metal complexes, and related derivatives have been investigated for their use as dyes in histology and as components of multimodal imaging probes. The photophysical properties of porphyrin–metal complexes featuring radiometals have been a focus of our attention for the realization of fluorescence imaging probes coupled with radioimaging capabilities and therapeutic potential having “true” theranostic promise. We report hereby on the synthesis, radiochemistry, structural investigations, and preliminary in vitroand in vivouptake studies on a range of functionalized porphyrin-based derivatives. In pursuit of developing new porphyrin-based probes for multimodality imaging applications, we report new functionalized neutral, polycationic, and polyanionic porphyrins incorporating nitroimidazole and sulfonamide moieties, which were used as targeting groups to improve the notoriously poor pharmacokinetics of porphyrin tags. The resulting functional metalloporphyrin species were stable under serum challenges and the nitroimidazole and sulfonamide derivatives remained fluorescent, allowing in vitroconfocal studies and visualization of the lysosomal uptake in a gallium(III) sulfonamide derivative. The molecular structures of selected porphyrin derivatives were determined by single crystal X-ray diffraction using synchrotron radiation. We also investigated the nature of the emission/excitation behavior of model functional porphyrins using in silicoapproaches such as TD DFT in simple solvation models. The conjugation of porphyrins with the [7-13] and [7-14] fragments of bombesin was also achieved, to provide targeting of the gastrin releasing peptide receptor (GRPR). Depending on the metal, probe conjugates of relevance for single photon emission computed tomography (SPECT) or positron emission tomography (PET) probes have been designed and tested hereby, using TPP and related functional free base porphyrins as the bifunctional chelator synthetic scaffold and 111In[In] or 68Ga[Ga], respectively, as the central metal ions. Interestingly, for simple porphyrin conjugates good radiochemical incorporation was obtained for both radiometals, but the presence of peptides significantly diminished the radio-incorporation yields. Although the gallium-68 radiochemistry of the bombesin conjugates did not show radiochemical incorporation suitable for in vivostudies, likely because the presence of the peptide changed the behavior of the TPP-NH2synthon taken alone, the optical imaging assays indicated that the conjugated peptide tags do mediate uptake of the porphyrin units into cells.