Functionalised diphosphines for nuclear imaging via Pt(0)-catalysed hydrophosphination

  • Ailis C Chadwick

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


The use of P(III)-ligands in nuclear medicine is rare with only one clinical example called Myoview which is used for myocardial perfusion imaging and features two tetrofosmin ligands {(EtOCH2CH2)2PCH2CH2P(CH2CH2OEt)2} around a technetium-99m dioxo core. This thesis reports the synthesis of novel diphosphine ligands via a Pt(0)-catalysed hydrophosphination route for use as SPECT imaging agents. The Re(V) coordination chemistry of the ligands has been investigated as a model for Tc(V), before radiolabelling with 99mTc.

Bioconjugation is a technique used to covalently link ligands to biomolecules. The resultant bifunctional chelators allow for more selective imaging of disease and examples have been reported, though few have been used clinically. Bioconjugation of ligands described in this thesis to cyclic-RGDfk, a pentapeptide that is recognised by αvβ3 integrin receptors is detailed. αvβ3 integrin receptors play a role in the early stages of angiogenesis, an important stage in tumour development in which new blood vessels are formed which is depended on for growth. Targeting of such receptors with a bifunctional chelator would enable selective imaging of cancer.

Diphosphines with a maleic anhydride backbone have been synthesised for use as PET imaging agents. The presence of the anhydride moiety allows for efficient bioconjugation to cRGDfK peptides. A bis(dicyclohexylphosphino)maleic anhydride bioconjugate coordinates to radioactive copper-64 in high radiopurity. The biological properties of the complex including LogD7.4 and ex vivo biodistribution indicated that the imaging agent mostly likely accumulates in and clears the body via the liver. This is in contrast to the diphenylphosphino analogue which is more likely to be excreted via the kidneys.

In the final chapter, a Pt(0)-catalysed hydrophosphination route to novel functionalised diphosphines is reported. A range of ligands of type Ph2PCH2CH2P(CH2CH2Z)2 where Z = CO2Me, CO2Et, CO2tBu, CN, CONH2, CONMe2 or PO(OEt)2, have been synthesised and fully characterised. Platinum(0) chemistry and deuterium-labelling experiments as well as catalyst loading and rate investigations indicate that the mechanism of the reaction is similar to that of the previously reported Pt(0)-catalysed hydrophosphination by monophosphines. Oxidative addition is followed by a P-C bond forming Michael addition step before intramolecular C-H bond formation and then dissociation of the product.

All new compounds have been characterised by a combination of 31P, 1H, 13C, 2H and 195Pt NMR spectroscopy, IR spectroscopy, mass spectrometry and X-ray crystallography.
Date of Award23 Jan 2020
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorPaul G Pringle (Supervisor)

Cite this