Dustin Wayne Demoin1, Ashley N Dame1, William D Minard2, Fabio Gallazzi3, Gary L Seickman4, Tammy L Rold5, Nicole Bernskoetter4, Michael E Fassbender6, Timothy J Hoffman7, Carol A Deakyne2, Silvia S Jurisson8. 1. Department of Chemistry, University of Missouri, Columbia, MO 65211, USA; Research Division, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA. 2. Department of Chemistry, University of Missouri, Columbia, MO 65211, USA. 3. Department of Structural Biology Core, University of Missouri, Columbia, MO 65211, USA. 4. Research Division, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA. 5. Department of Medicine, University of Missouri, Columbia, MO 65211, USA; Research Division, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA. 6. Chemistry Division, Los Alamos National Laboratory, PO Box 1663, Los Alamos, NM 87545, USA. 7. Department of Chemistry, University of Missouri, Columbia, MO 65211, USA; Department of Medicine, University of Missouri, Columbia, MO 65211, USA; Research Division, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA. 8. Department of Chemistry, University of Missouri, Columbia, MO 65211, USA. Electronic address: jurissons@missouri.edu.
Abstract
INTRODUCTION: Targeted radiotherapy using the bifunctional chelate approach with 186/188Re(V) is challenging because of the susceptibility of monooxorhenium(V)-based complexes to oxidize in vivo at high dilution. A monoamine-monoamide dithiol (MAMA)-based bifunctional chelating agent was evaluated with both rhenium and technetium to determine its utility for in vivo applications. METHODS: A 222-MAMA chelator, 222-MAMA(N-6-Ahx-OEt) bifunctional chelator, and 222-MAMA(N-6-Ahx-BBN(7-14)NH2) were synthesized, complexed with rhenium, radiolabeled with 99mTc and 186Re (carrier added and no carrier added), and evaluated in initial biological distribution studies. RESULTS: An IC50 value of 2.0±0.7nM for natReO-222-MAMA(N-6-Ahx-BBN(7-14)NH2) compared to [125I]-Tyr4-BBN(NH2) was determined through competitive cell binding assays with PC-3 tumor cells. In vivo evaluation of the no-carrier added 99mTc-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed little gastric uptake and blockable pancreatic uptake in normal mice. CONCLUSIONS: The 186ReO-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed stability in biological media, which indicates that the 222-N2S2 chelator is appropriate for chelating 186/188Re in radiopharmaceuticals involving peptides. Additionally, the in vitro cell studies showed that the ReO-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex (macroscopically) bound to PC3-tumor cell surface receptors with high affinity. The 99mTc analog was stable in vivo and exhibited pancreatic uptake in mice that was blockable, indicating BB2r targeting.
INTRODUCTION: Targeted radiotherapy using the bifunctionn class="Chemical">al chelate approach with 186/188Re(V) is challenging because of the susceptibility of monooxorhenium(V)-based complexes to oxidize in vivo at high dilution. A monoamine-monoamide dithiol (MAMA)-based bifunctional chelating agent was evaluated with both rhenium and technetium to determine its utility for in vivo applications. METHODS: A 222-MAMA chelator, 222-MAMA(N-6-Ahx-OEt) bifunctional chelator, and 222-MAMA(N-6-Ahx-BBN(7-14)NH2) were synthesized, complexed with rhenium, radiolabeled with 99mTc and 186Re (carrier added and no carrier added), and evaluated in initial biological distribution studies. RESULTS: An IC50 value of 2.0±0.7nM for natReO-222-MAMA(N-6-Ahx-BBN(7-14)NH2) compared to [125I]-Tyr4-BBN(NH2) was determined through competitive cell binding assays with PC-3tumor cells. In vivo evaluation of the no-carrier added 99mTc-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed little gastric uptake and blockable pancreatic uptake in normalmice. CONCLUSIONS: The 186ReO-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed stability in biological media, which indicates that the 222-N2S2 chelator is appropriate for chelating 186/188Re in radiopharmaceuticals involving peptides. Additionally, the in vitro cell studies showed that the ReO-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex (macroscopically) bound to PC3-tumor cell surface receptors with high affinity. The 99mTc analog was stable in vivo and exhibited pancreatic uptake in mice that was blockable, indicating BB2r targeting.
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