Development and biodistribution studies of 77As-labeled trithiol RM2 bioconjugates for prostate cancer: Comparison of [77As]As-trithiol-Ser-Ser-RM2 vs. [77As]As-trithiol-Glu-Ser-RM2

Li Ma; Cameron Grant; Fabio Gallazzi; Lisa D Watkinson; Terry L Carmack; Mary F Embree; C Jeff Smith; Dmitri Medvedev; Cathy S Cutler; Yawen Li; D Scott Wilbur; Heather M Hennkens; Silvia S Jurisson

doi:10.1016/j.nucmedbio.2022.03.003

Development and biodistribution studies of ⁷⁷As-labeled trithiol RM2 bioconjugates for prostate cancer: Comparison of [⁷⁷As]As-trithiol-Ser-Ser-RM2 vs. [⁷⁷As]As-trithiol-Glu-Ser-RM2

Nucl Med Biol. 2022 May-Jun:108-109:61-69. doi: 10.1016/j.nucmedbio.2022.03.003. Epub 2022 Mar 16.

Authors

Affiliations

¹ Department of Chemistry, University of Missouri, Columbia, MO 65211, USA.
² Department of Chemistry, University of Missouri, Columbia, MO 65211, USA; Molecular Interactions Core, University of Missouri, Columbia, MO 65211, USA.
³ Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA; Molecular Imaging and Theranostics Center, University of Missouri, Columbia, MO 65211, USA.
⁴ Research Reactor Center, University of Missouri, Columbia, MO 65211, USA.
⁵ Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA; Molecular Imaging and Theranostics Center, University of Missouri, Columbia, MO 65211, USA; Research Reactor Center, University of Missouri, Columbia, MO 65211, USA; Department of Radiology, University of Missouri, Columbia, MO 65211, USA.
⁶ Medical Isotope Research and Production Program (MIRP), Collider-Accelerator Department, Brookhaven National Laboratory, PO Box 5000, Building 801, Upton, NY 11973, USA.
⁷ Department of Radiation Oncology, University of Washington, Seattle, WA 98105, USA.
⁸ Department of Chemistry, University of Missouri, Columbia, MO 65211, USA; Molecular Imaging and Theranostics Center, University of Missouri, Columbia, MO 65211, USA; Research Reactor Center, University of Missouri, Columbia, MO 65211, USA.
⁹ Department of Chemistry, University of Missouri, Columbia, MO 65211, USA; Research Reactor Center, University of Missouri, Columbia, MO 65211, USA. Electronic address: [email protected].

PMID: 35325810
DOI: 10.1016/j.nucmedbio.2022.03.003

Abstract

Introduction: Recent progress with the production of ⁷²As (2.49 Mev β⁺_max (64%), 3.33 Mev β⁺_max (16%), 834 keV γ (81%), t_1/2: 26 h) and ⁷⁷As (0.683 Mev β^-_max (97%), 239 keV γ (1.59%), t_1/2: 38.8 h) has facilitated their evaluation as a potential "theranostic pair" for PET imaging and radiotherapy. Our 3rd generation trithiol chelate with two carboxylic acid groups was further developed as a bifunctional chelate for radioarsenic.

Methods: The As complex with the trithiol chelate was synthesized and characterized. No carrier added (nca) [⁷⁷As][H₂AsO₄^-] was used for radiolabeling studies. The trithiol chelate was conjugated to the RM2 peptide (_DPhe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂) via solid phase peptide synthesis with two different linkers, Ser-Ser and Glu-Ser. The trithiol chelate and its RM2 bioconjugates were radiolabeled with nca ⁷⁷As, and the RM2 bioconjugates were compared in initial biodistribution studies.

Results: The As diacid trithiol complex was characterized by ¹H NMR, ¹³C NMR and HR-ESI-MS. The trithiol-RM2 precursor and As trithiol bioconjugates were characterized by HR-ESI-MS and/or LC-ESI-MS. Radiolabeling of the RM2 bioconjugates with ⁷⁷As resulted in over 85% radiochemical yield for [⁷⁷As]As-trithiol-Ser-Ser-RM2 ([⁷⁷As]8) and 90% for [⁷⁷As]As-trithiol-Glu-Ser-RM2 ([⁷⁷As]9). Both radiotracers demonstrated excellent in vitro stability (≥ 90% remaining intact through 24 h in PBS buffer) and were more hydrophilic than previous analogues based on log D_7.4 values. Biodistribution results of the two radiotracers in healthy CF-1 male mice demonstrated blockable pancreatic uptake at 1 h (82% for ([⁷⁷As]8 and 78% for [⁷⁷As]9) indicating specific gastrin-releasing peptide receptor (GRPR) uptake. The primary route of excretion was through the gastrointestinal system for both radiotracers.

Conclusions: A new trithiol chelate with improved hydrophilicity was successfully conjugated to the RM2 peptide via two linkers, and high radiolabeling yield with nca ⁷⁷As was achieved. In vivo biodistribution studies with both radiotracers demonstrated blockable pancreatic uptake suggestive of specific receptor uptake.

Keywords: Arsenic-77; Biodistribution studies; RM2; Radiolabeling; Trithiol ligands.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Humans
Male
Mice
Positron-Emission Tomography / methods
Prostatic Neoplasms*
Radiopharmaceuticals
Receptors, Bombesin* / metabolism
Tissue Distribution

Substances

Radiopharmaceuticals
Receptors, Bombesin