Receptor-targeted peptide conjugates based on diphosphines enable preparation of 99mTc and 188Re theranostic agents for prostate cancer

Truc Pham; Ingebjorg Hungnes; Charlotte Rivas; Julie Cleaver; George Firth; Philip Blower; Jane Sosabowski; Gary Cook; Lefteris Livieratos; Jennifer Young; Paul G. Pringle; Michelle Ma

doi:10.2967/jnumed.124.267450

Receptor-targeted peptide conjugates based on diphosphines enable preparation of 99mTc and 188Re theranostic agents for prostate cancer

Truc Pham, Ingebjorg Hungnes, Charlotte Rivas, Julie Cleaver, George Firth, Philip Blower, Jane Sosabowski, Gary Cook, Lefteris Livieratos, Jennifer Young, Paul G. Pringle, Michelle Ma

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Abstract

Benchtop ⁹⁹Mo/ ^99mTc and ¹⁸⁸W/ ¹⁸⁸Re generators enable economical production of molecular theranostic ^99mTc and ¹⁸⁸Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates ^99mTc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)–targeted peptide with ^99mTc and ¹⁸⁸Re for diagnostic imaging and systemic radiotherapy of prostate cancer. Methods: Two diphosphine-dipeptide bioconjugates, DP1-PSMAt and DP2-PSMAt, were formulated into kits for radiolabeling with ^99mTc and ¹⁸⁸Re. The resulting radiotracers were studied in vitro, in prostate cancer cells, and in vivo in mouse xenograft models, to assess similarity of uptake and biodistribution for each ^99mTc/ ¹⁸⁸Re pair of agents. Results: Both DP1-PSMAt and DP2-PSMAt could be efficiently radiolabeled with ^99mTc and ¹⁸⁸Re using kit-based methods to furnish the isostructural compounds MDP1-PSMAt and M-DP2-PSMAt (M 5 [ ^99mTc]Tc, [ ¹⁸⁸Re]Re). All ^99mTc/ ¹⁸⁸Re radiotracers demonstrated specific uptake in PSMA-expressing prostate cancer cells, with negligible uptake in prostate cancer cells that did not express PSMA or in which PSMA uptake was blocked. M-DP1-PSMAt and M-DP2-PSMAt also exhibited high tumor uptake (18–30 percentage injected dose per gram at 2 h after injection), low retention in nontarget organs, fast blood clearance, and excretion predominantly via a renal pathway. Importantly, each pair of ^99mTc/ ¹⁸⁸Re radiotracers showed near-identical biologic behavior in these experiments. Conclusion: We have prepared and developed novel pairs of isostructural PSMA-targeting ^99mTc/ ¹⁸⁸Re theranostic agents. These generator-based theranostic agents have potential to provide access to the benefits of PSMA-targeted diagnostic imaging and systemic radiotherapy in health care settings that do not routinely have access to either reactor-produced ¹⁷⁷Lu radiopharmaceuticals or PET/CT infrastructure.

Original language	English
Pages (from-to)	1087-1094
Number of pages	8
Journal	Journal of Nuclear Medicine
Volume	65
Issue number	7
Early online date	6 Jun 2024
DOIs	https://doi.org/10.2967/jnumed.124.267450
Publication status	Published - 1 Jul 2024

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Manuscript - Tc-DP-PSMA biological data_V20_preprintAccepted author manuscript, 4.52 MBLicence: CC BY
jnumed.124.267450.fullOther version, 1.45 MBLicence: CC BY

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Pham, T., Hungnes, I., Rivas, C., Cleaver, J., Firth, G., Blower, P., Sosabowski, J., Cook, G., Livieratos, L., Young, J., Pringle, P. G., & Ma, M. (2024). Receptor-targeted peptide conjugates based on diphosphines enable preparation of 99mTc and 188Re theranostic agents for prostate cancer. Journal of Nuclear Medicine, 65(7), 1087-1094. https://doi.org/10.2967/jnumed.124.267450

@article{abe1a104aeae4705a53ea556a5d4a0ec,

title = "Receptor-targeted peptide conjugates based on diphosphines enable preparation of 99mTc and 188Re theranostic agents for prostate cancer",

abstract = "Benchtop 99Mo/ 99mTc and 188W/ 188Re generators enable economical production of molecular theranostic 99mTc and 188Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates 99mTc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)–targeted peptide with 99mTc and 188Re for diagnostic imaging and systemic radiotherapy of prostate cancer. Methods: Two diphosphine-dipeptide bioconjugates, DP1-PSMAt and DP2-PSMAt, were formulated into kits for radiolabeling with 99mTc and 188Re. The resulting radiotracers were studied in vitro, in prostate cancer cells, and in vivo in mouse xenograft models, to assess similarity of uptake and biodistribution for each 99mTc/ 188Re pair of agents. Results: Both DP1-PSMAt and DP2-PSMAt could be efficiently radiolabeled with 99mTc and 188Re using kit-based methods to furnish the isostructural compounds MDP1-PSMAt and M-DP2-PSMAt (M 5 [ 99mTc]Tc, [ 188Re]Re). All 99mTc/ 188Re radiotracers demonstrated specific uptake in PSMA-expressing prostate cancer cells, with negligible uptake in prostate cancer cells that did not express PSMA or in which PSMA uptake was blocked. M-DP1-PSMAt and M-DP2-PSMAt also exhibited high tumor uptake (18–30 percentage injected dose per gram at 2 h after injection), low retention in nontarget organs, fast blood clearance, and excretion predominantly via a renal pathway. Importantly, each pair of 99mTc/ 188Re radiotracers showed near-identical biologic behavior in these experiments. Conclusion: We have prepared and developed novel pairs of isostructural PSMA-targeting 99mTc/ 188Re theranostic agents. These generator-based theranostic agents have potential to provide access to the benefits of PSMA-targeted diagnostic imaging and systemic radiotherapy in health care settings that do not routinely have access to either reactor-produced 177Lu radiopharmaceuticals or PET/CT infrastructure.",

author = "Truc Pham and Ingebjorg Hungnes and Charlotte Rivas and Julie Cleaver and George Firth and Philip Blower and Jane Sosabowski and Gary Cook and Lefteris Livieratos and Jennifer Young and Pringle, {Paul G.} and Michelle Ma",

year = "2024",

month = jul,

day = "1",

doi = "10.2967/jnumed.124.267450",

language = "English",

volume = "65",

pages = "1087--1094",

journal = "Journal of Nuclear Medicine",

issn = "0161-5505",

publisher = "Society of Nuclear Medicine Inc.",

number = "7",

}

Pham, T , Hungnes, I , Rivas, C, Cleaver, J, Firth, G , Blower, P, Sosabowski, J, Cook, G , Livieratos, L , Young, J, Pringle, PG & Ma, M 2024, 'Receptor-targeted peptide conjugates based on diphosphines enable preparation of 99mTc and 188Re theranostic agents for prostate cancer', Journal of Nuclear Medicine, vol. 65, no. 7, pp. 1087-1094. https://doi.org/10.2967/jnumed.124.267450

TY - JOUR

T1 - Receptor-targeted peptide conjugates based on diphosphines enable preparation of 99mTc and 188Re theranostic agents for prostate cancer

AU - Pham, Truc

AU - Hungnes, Ingebjorg

AU - Rivas, Charlotte

AU - Cleaver, Julie

AU - Firth, George

AU - Blower, Philip

AU - Sosabowski, Jane

AU - Cook, Gary

AU - Livieratos, Lefteris

AU - Young, Jennifer

AU - Pringle, Paul G.

AU - Ma, Michelle

PY - 2024/7/1

Y1 - 2024/7/1

N2 - Benchtop 99Mo/ 99mTc and 188W/ 188Re generators enable economical production of molecular theranostic 99mTc and 188Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates 99mTc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)–targeted peptide with 99mTc and 188Re for diagnostic imaging and systemic radiotherapy of prostate cancer. Methods: Two diphosphine-dipeptide bioconjugates, DP1-PSMAt and DP2-PSMAt, were formulated into kits for radiolabeling with 99mTc and 188Re. The resulting radiotracers were studied in vitro, in prostate cancer cells, and in vivo in mouse xenograft models, to assess similarity of uptake and biodistribution for each 99mTc/ 188Re pair of agents. Results: Both DP1-PSMAt and DP2-PSMAt could be efficiently radiolabeled with 99mTc and 188Re using kit-based methods to furnish the isostructural compounds MDP1-PSMAt and M-DP2-PSMAt (M 5 [ 99mTc]Tc, [ 188Re]Re). All 99mTc/ 188Re radiotracers demonstrated specific uptake in PSMA-expressing prostate cancer cells, with negligible uptake in prostate cancer cells that did not express PSMA or in which PSMA uptake was blocked. M-DP1-PSMAt and M-DP2-PSMAt also exhibited high tumor uptake (18–30 percentage injected dose per gram at 2 h after injection), low retention in nontarget organs, fast blood clearance, and excretion predominantly via a renal pathway. Importantly, each pair of 99mTc/ 188Re radiotracers showed near-identical biologic behavior in these experiments. Conclusion: We have prepared and developed novel pairs of isostructural PSMA-targeting 99mTc/ 188Re theranostic agents. These generator-based theranostic agents have potential to provide access to the benefits of PSMA-targeted diagnostic imaging and systemic radiotherapy in health care settings that do not routinely have access to either reactor-produced 177Lu radiopharmaceuticals or PET/CT infrastructure.

AB - Benchtop 99Mo/ 99mTc and 188W/ 188Re generators enable economical production of molecular theranostic 99mTc and 188Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates 99mTc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)–targeted peptide with 99mTc and 188Re for diagnostic imaging and systemic radiotherapy of prostate cancer. Methods: Two diphosphine-dipeptide bioconjugates, DP1-PSMAt and DP2-PSMAt, were formulated into kits for radiolabeling with 99mTc and 188Re. The resulting radiotracers were studied in vitro, in prostate cancer cells, and in vivo in mouse xenograft models, to assess similarity of uptake and biodistribution for each 99mTc/ 188Re pair of agents. Results: Both DP1-PSMAt and DP2-PSMAt could be efficiently radiolabeled with 99mTc and 188Re using kit-based methods to furnish the isostructural compounds MDP1-PSMAt and M-DP2-PSMAt (M 5 [ 99mTc]Tc, [ 188Re]Re). All 99mTc/ 188Re radiotracers demonstrated specific uptake in PSMA-expressing prostate cancer cells, with negligible uptake in prostate cancer cells that did not express PSMA or in which PSMA uptake was blocked. M-DP1-PSMAt and M-DP2-PSMAt also exhibited high tumor uptake (18–30 percentage injected dose per gram at 2 h after injection), low retention in nontarget organs, fast blood clearance, and excretion predominantly via a renal pathway. Importantly, each pair of 99mTc/ 188Re radiotracers showed near-identical biologic behavior in these experiments. Conclusion: We have prepared and developed novel pairs of isostructural PSMA-targeting 99mTc/ 188Re theranostic agents. These generator-based theranostic agents have potential to provide access to the benefits of PSMA-targeted diagnostic imaging and systemic radiotherapy in health care settings that do not routinely have access to either reactor-produced 177Lu radiopharmaceuticals or PET/CT infrastructure.

UR - http://www.scopus.com/inward/record.url?scp=85198033563&partnerID=8YFLogxK

U2 - 10.2967/jnumed.124.267450

DO - 10.2967/jnumed.124.267450

M3 - Article

C2 - 38844360

SN - 0161-5505

VL - 65

SP - 1087

EP - 1094

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

IS - 7

ER -

Receptor-targeted peptide conjugates based on diphosphines enable preparation of 99mTc and 188Re theranostic agents for prostate cancer

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