Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules

Rachel E Nuttall; Truc Thuy Pham; Ailis C Chadwick; Ingebjørg N Hungnes; George Firth; Martin A Heckenast; Hazel A Sparkes; M Carmen Galan; Michelle T Ma; Paul G Pringle

doi:10.1021/acs.inorgchem.2c04008

Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules

Rachel E Nuttall
, Truc Thuy Pham
, Ailis C Chadwick
, Ingebjørg N Hungnes
, George Firth
, Martin A Heckenast
, Hazel A Sparkes
, M Carmen Galan^*
, Michelle T Ma^*
, Paul G Pringle^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

10 Citations (Scopus)

Abstract

The ability to append targeting biomolecules to chelators that efficiently coordinate to the diagnostic imaging radionuclide, 99mTc, and the therapeutic radionuclide, 188Re, can potentially enable receptor-targeted "theranostic" treatment of disease. Here we show that Pt(0)-catalyzed hydrophosphination reactions are well-suited to the derivatization of diphosphines with biomolecular moieties enabling the efficient synthesis of ligands of the type Ph 2PCH 2CH 2P(CH 2CH 2-Glc) 2 ( L, where Glc = a glucose moiety) using the readily accessible Ph 2PCH 2CH 2PH 2 and acryl derivatives. It is shown that hydrophosphination of an acrylate derivative of a deprotected glucose can be carried out in aqueous media. Furthermore, the resulting glucose-chelator conjugates can be radiolabeled with either 99mTc(V) or 188Re(V) in high radiochemical yields (>95%), to furnish separable mixtures of cis- and trans-[M(O) 2 L 2] + (M = Tc, Re). Single photon emission computed tomography (SPECT) imaging and ex vivo biodistribution in healthy mice show that each isomer possesses favorable pharmacokinetic properties, with rapid clearance from blood circulation via a renal pathway. Both cis-[ 99mTc(O) 2 L 2] + and trans-[ 99mTc(O) 2 L 2] + exhibit high stability in serum. This new class of functionalized diphosphine chelators has the potential to provide access to receptor-targeted dual diagnostic/therapeutic pairs of radiopharmaceutical agents, for molecular 99mTc SPECT imaging and 188Re systemic radiotherapy.

Original language	English
Pages (from-to)	20582-20592
Number of pages	11
Journal	Inorganic Chemistry
Volume	62
Issue number	50
Early online date	31 Jan 2023
DOIs	https://doi.org/10.1021/acs.inorgchem.2c04008
Publication status	E-pub ahead of print - 31 Jan 2023

Bibliographical note

Funding Information:
This research was supported by a Cancer Research UK Career Establishment Award (C63178/A24959), the EPSRC programme for Next Generation Molecular Imaging and Therapy with Radionuclides (EP/S032789/1, “MITHRAS”), Rosetrees Trust (M685, M606), the Wellcome Multiuser Equipment Radioanalytical Facility funded by Wellcome Trust (212885/Z/18/Z), the Centre for Medical Engineering funded by the Wellcome Trust and the Engineering and Physical Sciences Research Council (EPSRC) (WT088641/Z/09/Z), the European Research Council grant number ERC–COG:648239, and the Bristol Chemical Synthesis Centre for Doctoral Training, funded by EPSRC (EP/L015366/1), and the University of Bristol, for a PhD studentship (to R.E.N.).We would like to thank Dr Paul J. Gates of the University of Bristol, UK for determining the mass spectra of the technetium complexes.

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.

Research Groups and Themes

BCS and TECS CDTs
Organic & Biological
Inorganic & Materials
Bristol BioDesign Institute

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Nuttall, R. E., Pham, T. T., Chadwick, A. C., Hungnes, I. N., Firth, G., Heckenast, M. A., Sparkes, H. A., Galan, M. C., Ma, M. T., & Pringle, P. G. (2023). Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules. Inorganic Chemistry, 62(50), 20582-20592. Advance online publication. https://doi.org/10.1021/acs.inorgchem.2c04008

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title = "Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules",

abstract = "The ability to append targeting biomolecules to chelators that efficiently coordinate to the diagnostic imaging radionuclide, 99mTc, and the therapeutic radionuclide, 188Re, can potentially enable receptor-targeted {"}theranostic{"} treatment of disease. Here we show that Pt(0)-catalyzed hydrophosphination reactions are well-suited to the derivatization of diphosphines with biomolecular moieties enabling the efficient synthesis of ligands of the type Ph 2PCH 2CH 2P(CH 2CH 2-Glc) 2 ( L, where Glc = a glucose moiety) using the readily accessible Ph 2PCH 2CH 2PH 2 and acryl derivatives. It is shown that hydrophosphination of an acrylate derivative of a deprotected glucose can be carried out in aqueous media. Furthermore, the resulting glucose-chelator conjugates can be radiolabeled with either 99mTc(V) or 188Re(V) in high radiochemical yields (>95\%), to furnish separable mixtures of cis- and trans-[M(O) 2 L 2] + (M = Tc, Re). Single photon emission computed tomography (SPECT) imaging and ex vivo biodistribution in healthy mice show that each isomer possesses favorable pharmacokinetic properties, with rapid clearance from blood circulation via a renal pathway. Both cis-[ 99mTc(O) 2 L 2] + and trans-[ 99mTc(O) 2 L 2] + exhibit high stability in serum. This new class of functionalized diphosphine chelators has the potential to provide access to receptor-targeted dual diagnostic/therapeutic pairs of radiopharmaceutical agents, for molecular 99mTc SPECT imaging and 188Re systemic radiotherapy. ",

author = "Nuttall, \{Rachel E\} and Pham, \{Truc Thuy\} and Chadwick, \{Ailis C\} and Hungnes, \{Ingebj{\o}rg N\} and George Firth and Heckenast, \{Martin A\} and Sparkes, \{Hazel A\} and Galan, \{M Carmen\} and Ma, \{Michelle T\} and Pringle, \{Paul G\}",

note = "Funding Information: This research was supported by a Cancer Research UK Career Establishment Award (C63178/A24959), the EPSRC programme for Next Generation Molecular Imaging and Therapy with Radionuclides (EP/S032789/1, “MITHRAS”), Rosetrees Trust (M685, M606), the Wellcome Multiuser Equipment Radioanalytical Facility funded by Wellcome Trust (212885/Z/18/Z), the Centre for Medical Engineering funded by the Wellcome Trust and the Engineering and Physical Sciences Research Council (EPSRC) (WT088641/Z/09/Z), the European Research Council grant number ERC–COG:648239, and the Bristol Chemical Synthesis Centre for Doctoral Training, funded by EPSRC (EP/L015366/1), and the University of Bristol, for a PhD studentship (to R.E.N.).We would like to thank Dr Paul J. Gates of the University of Bristol, UK for determining the mass spectra of the technetium complexes. Publisher Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society.",

year = "2023",

month = jan,

day = "31",

doi = "10.1021/acs.inorgchem.2c04008",

language = "English",

volume = "62",

pages = "20582--20592",

journal = "Inorganic Chemistry",

issn = "0020-1669",

publisher = "American Chemical Society",

number = "50",

}

Nuttall, RE, Pham, TT, Chadwick, AC, Hungnes, IN, Firth, G, Heckenast, MA, Sparkes, HA, Galan, MC, Ma, MT & Pringle, PG 2023, 'Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules', Inorganic Chemistry, vol. 62, no. 50, pp. 20582-20592. https://doi.org/10.1021/acs.inorgchem.2c04008

Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules. / Nuttall, Rachel E; Pham, Truc Thuy; Chadwick, Ailis C et al.
In: Inorganic Chemistry, Vol. 62, No. 50, 31.01.2023, p. 20582-20592.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules

AU - Nuttall, Rachel E

AU - Pham, Truc Thuy

AU - Chadwick, Ailis C

AU - Hungnes, Ingebjørg N

AU - Firth, George

AU - Heckenast, Martin A

AU - Sparkes, Hazel A

AU - Galan, M Carmen

AU - Ma, Michelle T

AU - Pringle, Paul G

N1 - Funding Information: This research was supported by a Cancer Research UK Career Establishment Award (C63178/A24959), the EPSRC programme for Next Generation Molecular Imaging and Therapy with Radionuclides (EP/S032789/1, “MITHRAS”), Rosetrees Trust (M685, M606), the Wellcome Multiuser Equipment Radioanalytical Facility funded by Wellcome Trust (212885/Z/18/Z), the Centre for Medical Engineering funded by the Wellcome Trust and the Engineering and Physical Sciences Research Council (EPSRC) (WT088641/Z/09/Z), the European Research Council grant number ERC–COG:648239, and the Bristol Chemical Synthesis Centre for Doctoral Training, funded by EPSRC (EP/L015366/1), and the University of Bristol, for a PhD studentship (to R.E.N.).We would like to thank Dr Paul J. Gates of the University of Bristol, UK for determining the mass spectra of the technetium complexes. Publisher Copyright: © 2023 The Authors. Published by American Chemical Society.

PY - 2023/1/31

Y1 - 2023/1/31

N2 - The ability to append targeting biomolecules to chelators that efficiently coordinate to the diagnostic imaging radionuclide, 99mTc, and the therapeutic radionuclide, 188Re, can potentially enable receptor-targeted "theranostic" treatment of disease. Here we show that Pt(0)-catalyzed hydrophosphination reactions are well-suited to the derivatization of diphosphines with biomolecular moieties enabling the efficient synthesis of ligands of the type Ph 2PCH 2CH 2P(CH 2CH 2-Glc) 2 ( L, where Glc = a glucose moiety) using the readily accessible Ph 2PCH 2CH 2PH 2 and acryl derivatives. It is shown that hydrophosphination of an acrylate derivative of a deprotected glucose can be carried out in aqueous media. Furthermore, the resulting glucose-chelator conjugates can be radiolabeled with either 99mTc(V) or 188Re(V) in high radiochemical yields (>95%), to furnish separable mixtures of cis- and trans-[M(O) 2 L 2] + (M = Tc, Re). Single photon emission computed tomography (SPECT) imaging and ex vivo biodistribution in healthy mice show that each isomer possesses favorable pharmacokinetic properties, with rapid clearance from blood circulation via a renal pathway. Both cis-[ 99mTc(O) 2 L 2] + and trans-[ 99mTc(O) 2 L 2] + exhibit high stability in serum. This new class of functionalized diphosphine chelators has the potential to provide access to receptor-targeted dual diagnostic/therapeutic pairs of radiopharmaceutical agents, for molecular 99mTc SPECT imaging and 188Re systemic radiotherapy.

AB - The ability to append targeting biomolecules to chelators that efficiently coordinate to the diagnostic imaging radionuclide, 99mTc, and the therapeutic radionuclide, 188Re, can potentially enable receptor-targeted "theranostic" treatment of disease. Here we show that Pt(0)-catalyzed hydrophosphination reactions are well-suited to the derivatization of diphosphines with biomolecular moieties enabling the efficient synthesis of ligands of the type Ph 2PCH 2CH 2P(CH 2CH 2-Glc) 2 ( L, where Glc = a glucose moiety) using the readily accessible Ph 2PCH 2CH 2PH 2 and acryl derivatives. It is shown that hydrophosphination of an acrylate derivative of a deprotected glucose can be carried out in aqueous media. Furthermore, the resulting glucose-chelator conjugates can be radiolabeled with either 99mTc(V) or 188Re(V) in high radiochemical yields (>95%), to furnish separable mixtures of cis- and trans-[M(O) 2 L 2] + (M = Tc, Re). Single photon emission computed tomography (SPECT) imaging and ex vivo biodistribution in healthy mice show that each isomer possesses favorable pharmacokinetic properties, with rapid clearance from blood circulation via a renal pathway. Both cis-[ 99mTc(O) 2 L 2] + and trans-[ 99mTc(O) 2 L 2] + exhibit high stability in serum. This new class of functionalized diphosphine chelators has the potential to provide access to receptor-targeted dual diagnostic/therapeutic pairs of radiopharmaceutical agents, for molecular 99mTc SPECT imaging and 188Re systemic radiotherapy.

U2 - 10.1021/acs.inorgchem.2c04008

DO - 10.1021/acs.inorgchem.2c04008

M3 - Article (Academic Journal)

C2 - 36719138

SN - 0020-1669

VL - 62

SP - 20582

EP - 20592

JO - Inorganic Chemistry

JF - Inorganic Chemistry

IS - 50

ER -

Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules

Abstract

Bibliographical note

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