Shining a light on medical diagnostics

Medical imaging potential for highly fluorescent Bodipy-phosphine complexes

Crystallographic data gathered at the Small Molecule Single Crystal Diffraction beamline (I19) have aided scientists from Newcastle University in characterising a series of metal complexes with potential applications in medical imaging and diagnostics for cancer.

Fluorescent metal complexes are used in diagnostic imaging of cells and in monitoring catalytic reactions because of the high sensitivity in detecting emission at low concentrations. This enables high spatial resolution in vitro at the sub-cellular level. There is currently a high level of interest in incorporating fluorescent markers into radiopharmaceuticals in order to obtain more accurate localisation information in imaging the probes both in vitro and in vivo.

Heavy metal complexes containing phosphine ligands are sought for medical purposes, based upon the discovery of gold(I), silver(I) and copper(I) phosphine compounds that show cytotoxic activity and significant anti-tumour properties. Gold, silver and copper compounds also have potential in nuclear medicine, where betaemitters such as 199Au and 111Ag can act as tracers, and positron emitter 64Cu is used in positron emission tomography (PET).

It has been shown that phosphine ligands in chromophores can act as fluorescence quenchers due to photoinduced electron transfer through a conjugation network. Researchers at Newcastle University investigated incorporating derivatives of the efficient and robust fluorophore Bodipy (boron-dipyrromethene) into a phosphine ligand. Their latest research reports the successful synthesis of fournovel C-Bodipy-containing tertiary phosphines 2a, 2b, 3a and 3b (Fig 1), where C-Bodipy is an aryl or alkyl substituted Bodipy. A mild synthetic route via the lithiation of Bodipy aryl bromides, followed by addition of the desired chlorophosphine resulted in yields of above 60% for the ligands shown. Subsequent complexation to copper, silver and gold resulted in formation of the metal complexes in almost quantitative yields.

Fig. 1: Synthesis of the C-Bodipy substituted tertiary phosphine derivatives. Davies et al. (2014) - Published by The Royal Society of Chemistry.

The monodentate tertiary phosphines were reacted with Cu(I), Ag(I) and Au(I) precursors to produce four complexes for each metal. Using Diamond’s I19 beamline in addition to local crystallographic facilities in Newcastle, the team solved the crystal structures for ligand 2a and nine of the synthesised complexes: three copper (one in two crystal forms), two silver and three gold compounds. For the majority, the structures display the expected geometry based on previous phosphine compounds of coinage metals. For the coppercontaining compound of ligand 3a (R=Ph, R’=Cy), two types of crystals were produced.

Structure A is a three-coordinate copper(I) Shining a light on medical diagnostics Medical imaging potential for highly fluorescent Bodipy-phosphine complexes complex with two phosphines and one acetonitrile ligand bound to the metal, whilst the PF-6 anion is non-coordinating. Structure B is also three-coordinate and has two phosphines bound but no coordination to the acetonitrile ligand; instead the PF-6 anion is weakly coordinated to the copper centre. Gold complexes are linear. Tetrahedral coordination of silver is highly distorted and in one case the potentially chelating hexafluoroacetylacetonate (hfa) ligand is attached to Ag with one short and one long Ag–O bond, giving a structure which is intermediate between three- and four-coordinate (Fig. 2). Small crystal size and structural disorder in this, the ligand itself, and one of the gold complexes meant that I19 was used to obtain the data required.

Fig. 2: View of the molecular structure of [Ag(3b)2(hfa)] with an unsymmetrically coordinated hfa ligand. Davies et al. (2014) - Published by The Royal Society of Chemistry.

Room-temperature fluorescence was recorded for all ligands, with λmax of 534/527 nm and 533/536 nm for ligands of type for 2a/2b and 4a/3b, respectively. High quantum yields were measured for 2b (0.29) and 3b (0.44), in particular, suggesting that the phosphine does not quench fluorescence, which contrasts with results from several existing phosphines. Furthermore, from the optical studies for the metal compounds, the high quantum yield of the free ligand is generally retained upon complexation. Quenching is less pronounced for the aryldialkylphosphine complexes of 3b compared to the triarylphosphine complexes of 2b and all three metal complexes containing ligand 3b have a higher quantum yield than the Bodipy precursor to the ligand.

These intriguing and encouraging photophysics results show the potential for Bodipy-containing phosphine ligands to be developed further. The excellent yields and mild route may be transferable to a wide range of chlorophosphines, leading to the possible synthesis of a library of Bodipy tertiary phosphines. This holds great promise for applications in medical imaging, especially given the anti-cancer properties of several other group 11 complexes. Future work will therefore focus on the use of these compounds in diagnostic imaging and therapy. They offer the potential to study the cellular fate of these molecules, by fluorescence, and therefore understand better their role in the body. Successful use of beamline I19 has been fundamental in the quest to prepare multi-modality biological imaging agents.

For more information about the I19 beamline, or to discuss potential applications, contact Principal Beamline Scientist Dr Dave Allan: dave.allan@diamond.ac.uk

 

Related publication:

Davies LH. et al. BR2BodPR2: highly fluorescent alternatives to PPh3 and PhPCy2. Dalton Transactions (2014). DOI: 10.1039/c4dt00704b

 

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