Preclinical evaluation of MC1R targeting theranostic pair [155Tb]Tb-crown-αMSH and [161Tb]Tb-crown-αMSH

Luke Wharton, Scott W. McNeil, Chengcheng Zhang, Gokce Engudar, Michiel Van de Voorde, Jutta Zeisler, Helena Koniar, Sathiya Sekar, Zheliang Yuan, Paul Schaffer, Valery Radchenko, Maarten Ooms, Peter Kunz, François Bénard, Hua Yang

Research outputpeer-review

Abstract

Background: Targeted radionuclide therapy is established as a highly effective strategy for the treatment of metastatic tumors; however, the co-development of suitable imaging companions to therapy remains significant challenge. Theranostic isotopes of terbium (149Tb, 152Tb, 155Tb, 161Tb) have the potential to provide chemically identical radionuclidic pairs, which collectively encompass all modes of nuclear decay relevant to nuclear medicine. Herein, we report the first radiochemistry and preclinical studies involving 155Tb- and 161Tb-labeled crown-αMSH, a small peptide-based bioconjugate suitable for targeting melanoma. Methods: 155Tb was produced via proton induced spallation of Ta targets using the isotope separation and acceleration facility at TRIUMF with isotope separation on-line (ISAC/ISOL). The radiolabeling characteristics of crown-αMSH with 155Tb and/or 161Tb were evaluated by concentration-dependence radiolabeling studies, and radio-HPLC stability studies. LogD7.4 measurements were obtained for [161Tb]Tb-crown-αMSH. Competitive binding assays were undertaken to determine the inhibition constant for [natTb]Tb-crown-αMSH in B16-F10 cells. Pre-clinical biodistribution and SPECT/CT imaging studies of 155Tb and 161Tb labeled crown-αMSH were undertaken in male C57Bl/6 J mice bearing B16-F10 melanoma tumors to evaluate tumor specific uptake and imaging potential for each radionuclide. Results: Quantitative radiolabeling of crown-αMSH with [155Tb]Tb3+ and [161Tb]Tb3+ was demonstrated under mild conditions (RT, 10 min) and low chelator concentrations; achieving high molar activities (23–29 MBq/nmol). Radio-HPLC studies showed [161Tb]Tb-crown-αMSH maintains excellent radiochemical purity in human serum, while gradual metabolic degradation is observed in mouse serum. Competitive binding assays showed the high affinity of [natTb]Tb-crown-αMSH toward MC1R. Two different methods for preparation of the [155Tb]Tb-crown-αMSH radiotracer were investigated and the impacts on the biodistribution profile in tumor bearing mice is compared. Preclinical in vivo studies of 155Tb- and 161Tb- labeled crown-αMSH were performed in parallel, in mice bearing B16-F10 tumors; where the biodistribution results showed similar tumor specific uptake (6.06–7.44 %IA/g at 2 h pi) and very low uptake in nontarget organs. These results were further corroborated through a series of single-photon emission computed tomography (SPECT) studies, with [155Tb]Tb-crown-αMSH and [161Tb]Tb-crown-αMSH showing comparable uptake profiles and excellent image contrast. Conclusions: Collectively, our studies highlight the promising characteristics of [155Tb]Tb-crown-αMSH and [161Tb]Tb-crown-αMSH as theranostic pair for nuclear imaging (155Tb) and radionuclide therapy (161Tb).

Original languageEnglish
Article number108925
Number of pages11
JournalNuclear Medicine and Biology
Volume136-137
DOIs
StatePublished - Sep 2024

Funding

This research was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) ( RGPIN-2022-03887 (HY), RGPIN-2018-04997 (VR)); TRIUMF receives federal funding via a contribution agreement with the National Research Council of Canada. This research was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN-2022-03887 (HY), RGPIN-2018-04997 (VR)) and Canadian Institutes of Health Research (CIHR) (480394); TRIUMF receives federal funding via a contribution agreement with the National Research Council of Canada.

FundersFunder number
NRC - National Research Council of Canada
NRC - National Research Council of CanadaRGPIN-2018-04997, RGPIN-2022-03887

    ASJC Scopus subject areas

    • Molecular Medicine
    • Radiology Nuclear Medicine and imaging
    • Cancer Research

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