We report the design and synthesis of new theranostic probes of relevance to non-communicable diseases (NCDs) such as prostate cancer (PCa). The need to diagnose this disease early as well as non-invasively remains a clinically unmet need. New synthetic fluorophores emitting in the far-red and near-infrared (NIR) regions of the electromagnetic spectrum are reported hereby. Our approach combines optical imaging in NIR with other molecular imaging modalities, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT). Here we present the synthesis, characterisation and applications for in vitro imaging of new conjugated keto-polymethines. The Figure shows the probes’ design which displays a central NIR emitting fluorophore (red), a ligand or prosthetic group for straightforward metal complexation and radiolabelling and a vector (blue) for targeting of PCa biomarkers. Synthetic pathways to new penta- and hepta-methine cyanine dyes incoporating metal chelators, such as bis-thiosemicarbazones ligands or functional siderophore models including DFO, and simultaneously feature solubilizing groups and peptide targeting moieties are discussed. New NIR emitting fluorescent dyes scaffolds were derivatised to incorporate biomolecular tags (e.g. glucose, nitroimidazoles, the peptide derivatives LysCoGlu or [7,13]bombesin fragments). Corresponding metal complexes (M = Cu(II), Ga(III) or Zr(IV)) were also synthesized and characterised as 'cold' models for corresponding PET tracers development. The proposed geometries and emission spectroscopy were explored computationally by TD DFT in gas phase and in solvent models. The behavior of these compounds in living cells was studied in living PC-3 prostate cancer cells by Fluorescence Lifetime Imaging Microscopy (FLIM), with laser excitation at 740 nm, coupled with single photon laser confocal microscopy which aided the evaluation of their behavior within cells, whereas FACS and MTT assays further elucidated their cellular activity.

Metal complexes and peptide conjugates of functional NIR emitting dyes: Synthetic scaffolds for multimodal imaging agents

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ACS Fall 2022

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