Glycoconjugated triphos ligands for radioimaging and radiotherapy

Abstract

The aim of this work was to synthesise a range of triphosphine ligands as bifunctional chelating agents for 99mTc and 188Re radiopharmaceuticals. Chapter 1 provides an overview of the relevant literature relating to nuclear medicine, carbohydrates and their links to cancer, theranostics, and hydrophosphination.

Chapter 2 describes the preparation of functionalised triphosphines using Pt(0)-catalysed hydrophosphination by triphosphine 2.1. Three novel tertiary triphosphines 2.3-2.5 were synthesised in high conversions of up to 95% with complete chemoselectivity for the anti-Markovnikov product. This showed the versatility of Pt(0)-catalysed hydrophosphination as a conjugation methodology. The ligands displayed characteristic AB2 spin patterns in their 31P{1H} NMR spectra and were coordinated to Pt(II), Mo(0), and Re(I), forming square planar or octahedral complexes.

The synthesis of four sugar precursors with triazole-acrylamide linkers (3.3, 3.5, 3.9, and 3.13) is described in Chapter 3 with overall yields of 9-40% across four steps. The precursors were prepared using a sequence of peracetylation, glycosylation, azidation and CuAAC click reactions, with glycosylation the lowest yielding step. These sugars were then applied in Pt(0)-catalysed hydrophosphination by triphosphine 2.1 to prepare four new triphosphine glycoconjugates in high NMR yields of 87-94%. Ligands 3.16 and 3.18 were chosen for 99mTc radiolabelling studies and acetyl protecting groups were removed to give 3.19 and 3.20.

Chapter 4 details the 99mTc radiolabelling of ligands 3.19 and 3.20 to form fac-[99mTc(CO)3(triphos)]+ complexes 4.1 and 4.2 in high radiochemical yields of >98%. The two step process was not as efficient as previously reported one-step processes, but offers the advantage of forming a single, well characterised isomer. Complexes 4.1 and 4.2 showed excellent stability in saline and PBS buffer (stable for 3 half-lives of 99mTc), but poorer stability in human serum (radiochemical purity of approx. 75% after 2 h). Further bioconjugation, radiolabelling and biological studies with 3.19 and 3.20 are planned.

Pt(0)-catalysed hydrophosphination has been shown to be a robust and efficient conjugation strategy, but the limits of the catalysis with respect to multidentate phosphines had not been explored. Chapter 5 presents the synthesis of 13 functionalised phosphines via Pt(0)-catalysed hydrophosphination including di-, tri-, tetra- and octa-phosphines. Three primary diphosphines 2.7, 5.1 and 2.6 with varying backbones were explored in Pt(0)-catalysed hydrophosphination, with results showing that the rate of hydrophosphination was a function of the alkene CH2=CHZ, in the order Z = CN > CO2tBu > CONMe2. Diphos 2.7 was more reactive than 5.1 and 2.6, but hydrophosphination by 2.6 was more chemoselective, with no telomers or phospha-Michael by-products detected. The synthesis of triphosphines 5.2a,b, tetraphosphines 5.3a,b, and octaphosphines 5.4a,b demonstrated the remarkable tolerance of Pt(0)-catalysed hydrophosphination to the presence of multidentate phosphines. As yet, none of these phosphines have been applied in nuclear medicine, but exploring their use in targeted radiopharmaceuticals is an important future goal.

Additional details are provided in the executive summary in Chapter 6.

Date of Award	17 Mar 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Paul G Pringle (Supervisor), M C Galan (Supervisor), Natalie Fey (Supervisor) & Michelle Ma (Supervisor)