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

7 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.

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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",

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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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