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Title: A trithiol bifunctional chelate for 72,77As: A matched pair theranostic complex with high in vivo stability

Abstract

Trithiol chelates are suitable for labeling radioarsenic ( 72As: 2.49 MeV β +, 26 h; 77As: 0.683 MeV β -, 38.8 h) to form potential theranostic radiopharmaceuticals for PET imaging and therapy. In this paper, to investigate the in vivo stability of trithiol chelates complexed with no carrier added (nca) radioarsenic, a bifunctional trithiol chelate was developed, and conjugated to bombesin(7–14)NH 2 as a model peptide. A trithiol-BBN(7–14)NH 2 bioconjugate and its arsenic complex were synthesized and characterized. The trithiol-BBN(7–14)NH 2 conjugate was radiolabeled with 77As, its in vitro stability assessed, and biodistribution studies were performed in CF-1 normal mice of free [ 77As]arsenate and 77As-trithiol- BBN(7–14)NH 2. The trithiol-BBN(7–14)NH 2 conjugate, its precursors and its As-trithiol-BBN(7–14)NH 2 complex were fully characterized. Radiolabeling studies with nca 77As resulted in over 90% radiochemical yield of 77As-trithiol-BBN, which was stable for over 48 h. Biodistribution studies were performed with both free [ 77As]arsenate and Sep-Pak® purified 77As-trithiol-BBN(7–14)NH 2. Compared to the fast renal clearance of free [ 77As]arsenate, 77As-trithiol-BBN(7–14)NH 2 demonstrated increased retention with clearance mainly through the hepatobiliary system, consistent with the lipophilicity of the 77As-trithiol-BBN(714)NH 2 complex. Finally, the combined in vitro stability of 77As-trithiol-BBN(7–14)NH 2 and the biodistribution resultsmore » demonstrate its high in vivo stability, making the trithiol a promising platform for developing radioarsenic-based theranostic radiopharmaceuticals.« less

Authors:
 [1];  [2];  [1];  [3];  [1];  [4];  [1];  [5];  [6];  [3]; ORCiD logo [7]
  1. Univ. of Missouri, Columbia, MO (United States). Dept. of Chemistry
  2. Univ. of Missouri, Columbia, MO (United States). Dept. of Chemistry; Brookhaven National Lab. (BNL), Upton, NY (United States). Medical Isotope Research and Production Program (MIRP). Collider-Accelerator Dept.
  3. Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (United States). Research Service
  4. Univ. of Missouri, Columbia, MO (United States). Molecular Interaction Core
  5. Univ. of Missouri, Columbia, MO (United States). Research Reactor Center (MURR); Brookhaven National Lab. (BNL), Upton, NY (United States). Medical Isotope Research and Production Program (MIRP). Collider-Accelerator Dept.
  6. Univ. of Missouri, Columbia, MO (United States). Research Reactor Center (MURR)
  7. Univ. of Missouri, Columbia, MO (United States). Dept. of Chemistry. Research Reactor Center (MURR)
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States); Univ. of Missouri, Columbia, MO (United States); Harry S. Truman Memorial Veterans' Hospital, Columbia, MO (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Nuclear Physics (NP) (SC-26); National Inst. of Health (NIH) (United States); Dept. of Veterans Affairs (VA) (United States)
OSTI Identifier:
1464108
Report Number(s):
BNL-207952-2018-JAAM
Journal ID: ISSN 0969-8051
Grant/Contract Number:  
SC0012704; SC0003851; SC0010283; 5 T32-EB004822
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nuclear Medicine and Biology
Additional Journal Information:
Journal Volume: 61; Journal ID: ISSN 0969-8051
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; 62 RADIOLOGY AND NUCLEAR MEDICINE; trithiol bioconjugate; arsenic trithiol; no carrier added 77As; radiolabeling; biodistributions

Citation Formats

Feng, Yutian, DeGraffenreid, Anthony J., Phipps, Michael D., Rold, Tammy L., Okoye, Nkemakonam C., Gallazzi, Fabio A., Barnes, Charles L., Cutler, Cathy S., Ketring, Alan R., Hoffman, Timothy J., and Jurisson, Silvia S. A trithiol bifunctional chelate for 72,77As: A matched pair theranostic complex with high in vivo stability. United States: N. p., 2018. Web. doi:10.1016/j.nucmedbio.2018.03.001.
Feng, Yutian, DeGraffenreid, Anthony J., Phipps, Michael D., Rold, Tammy L., Okoye, Nkemakonam C., Gallazzi, Fabio A., Barnes, Charles L., Cutler, Cathy S., Ketring, Alan R., Hoffman, Timothy J., & Jurisson, Silvia S. A trithiol bifunctional chelate for 72,77As: A matched pair theranostic complex with high in vivo stability. United States. doi:10.1016/j.nucmedbio.2018.03.001.
Feng, Yutian, DeGraffenreid, Anthony J., Phipps, Michael D., Rold, Tammy L., Okoye, Nkemakonam C., Gallazzi, Fabio A., Barnes, Charles L., Cutler, Cathy S., Ketring, Alan R., Hoffman, Timothy J., and Jurisson, Silvia S. Sat . "A trithiol bifunctional chelate for 72,77As: A matched pair theranostic complex with high in vivo stability". United States. doi:10.1016/j.nucmedbio.2018.03.001.
@article{osti_1464108,
title = {A trithiol bifunctional chelate for 72,77As: A matched pair theranostic complex with high in vivo stability},
author = {Feng, Yutian and DeGraffenreid, Anthony J. and Phipps, Michael D. and Rold, Tammy L. and Okoye, Nkemakonam C. and Gallazzi, Fabio A. and Barnes, Charles L. and Cutler, Cathy S. and Ketring, Alan R. and Hoffman, Timothy J. and Jurisson, Silvia S.},
abstractNote = {Trithiol chelates are suitable for labeling radioarsenic (72As: 2.49 MeV β+, 26 h; 77As: 0.683 MeV β-, 38.8 h) to form potential theranostic radiopharmaceuticals for PET imaging and therapy. In this paper, to investigate the in vivo stability of trithiol chelates complexed with no carrier added (nca) radioarsenic, a bifunctional trithiol chelate was developed, and conjugated to bombesin(7–14)NH2 as a model peptide. A trithiol-BBN(7–14)NH2 bioconjugate and its arsenic complex were synthesized and characterized. The trithiol-BBN(7–14)NH2 conjugate was radiolabeled with 77As, its in vitro stability assessed, and biodistribution studies were performed in CF-1 normal mice of free [77As]arsenate and 77As-trithiol- BBN(7–14)NH2. The trithiol-BBN(7–14)NH2 conjugate, its precursors and its As-trithiol-BBN(7–14)NH2 complex were fully characterized. Radiolabeling studies with nca 77As resulted in over 90% radiochemical yield of 77As-trithiol-BBN, which was stable for over 48 h. Biodistribution studies were performed with both free [77As]arsenate and Sep-Pak® purified 77As-trithiol-BBN(7–14)NH2. Compared to the fast renal clearance of free [77As]arsenate, 77As-trithiol-BBN(7–14)NH2 demonstrated increased retention with clearance mainly through the hepatobiliary system, consistent with the lipophilicity of the 77As-trithiol-BBN(714)NH2 complex. Finally, the combined in vitro stability of 77As-trithiol-BBN(7–14)NH2 and the biodistribution results demonstrate its high in vivo stability, making the trithiol a promising platform for developing radioarsenic-based theranostic radiopharmaceuticals.},
doi = {10.1016/j.nucmedbio.2018.03.001},
journal = {Nuclear Medicine and Biology},
number = ,
volume = 61,
place = {United States},
year = {Sat Mar 10 00:00:00 EST 2018},
month = {Sat Mar 10 00:00:00 EST 2018}
}

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