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

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

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

Journal Article · Wed Mar 16 00:00:00 EDT 2022 · Nuclear Medicine and Biology

DOI:https://doi.org/10.1016/j.nucmedbio.2022.03.003· OSTI ID:1854922

Ma, Li ^[1]; Grant, Cameron ^[2]; Gallazzi, Fabio ^[2]; Watkinson, Lisa D. ^[3]; Carmack, Terry L. ^[3]; Embree, Mary F. ^[2]; Smith, C. Jeff ^[3]; Medvedev, Dmitri ^[4]; Cutler, Cathy S. ^[4]; Li, Yawen ^[5]; Wilbur, D. Scott ^[5]; Hennkens, Heather M. ^[2]; Jurisson, Silvia S. ^[2]

Univ. of Missouri, Columbia, MO (United States); University of Missouri
Univ. of Missouri, Columbia, MO (United States)
Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (United States); Univ. of Missouri, Columbia, MO (United States)
Brookhaven National Lab. (BNL), Upton, NY (United States)
Univ. of Washington, Seattle, WA (United States)

Recent progress with the production of ⁷²As (2.49 Mev β⁺_max (64%), 3.33 Mev β⁺_max (16%), 834 keV (81%), t_1/2: 26 h) and ⁷⁷As (0.683 Mev β-_max (97%), 239 keV (1.59%), t_1/2: 38.8 h) has facilitated their evaluation as a potential “theranostic pair” for PET imaging and radiotherapy. Our 3^rd generation trithiol chelate with two carboxylic acid groups was further developed as a bifunctional chelate for radioarsenic. The As complex with the trithiol chelate was synthesized and characterized. No carrier added (nca) [⁷⁷As][H₂AsO₄^-] was used for radiolabeling studies. Here, the trithiol chelate was conjugated to the RM2 peptide (DPhe-Gln-Trp-Ala-VaI-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. 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. 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.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of Missouri, Columbia, MO (United States)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC), Nuclear Physics (NP)

Grant/Contract Number:: SC0010283; SC0020159

OSTI ID:: 1854922

Alternate ID(s):: OSTI ID: 1855874

Journal Information:: Nuclear Medicine and Biology, Journal Name: Nuclear Medicine and Biology Vol. 108-109; ISSN 0969-8051

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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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

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