Monooxorhenium(V) complexes with 222-N2S2MAMA ligands for bifunctional chelator agents: Syntheses and preliminary in vivo evaluation.
BACKGROUND
Targeted radiotherapy using the bifunctional chelate approach with186/188Re(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 with99mTc and186Re (carrier added and no carrier added), and evaluated in initial biological distribution studies.


RESULTS
An IC50value of 2.0±0.7nM fornatReO-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 added99mTc-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed little gastric uptake and blockable pancreatic uptake in normal mice.


CONCLUSIONS
The186ReO-222-N2S2(N-6-Ahx-BBN(7-14)NH2) complex showed stability in biological media, which indicates that the 222-N2S2chelator is appropriate for chelating186/188Re 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. The99mTc analog was stable in vivo and exhibited pancreatic uptake in mice that was blockable, indicating BB2r targeting.
Department of Chemistry, University of Missouri, Columbia, MO 65211, USA; Research Division, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA.
Dustin Wayne
DW
Demoin
Department of Chemistry, University of Missouri, Columbia, MO 65211, USA; Research Division, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA.
Ashley N
AN
Dame
Department of Chemistry, University of Missouri, Columbia, MO 65211, USA.
William D
WD
Minard
Department of Structural Biology Core, University of Missouri, Columbia, MO 65211, USA.
Fabio
F
Gallazzi
Research Division, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA.
Gary L
GL
Seickman
Department of Medicine, University of Missouri, Columbia, MO 65211, USA; Research Division, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA.
Tammy L
TL
Rold
Research Division, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA.
Nicole
N
Bernskoetter
Chemistry Division, Los Alamos National Laboratory, PO Box 1663, Los Alamos, NM 87545, USA.
Michael E
ME
Fassbender
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.
Timothy J
TJ
Hoffman
Department of Chemistry, University of Missouri, Columbia, MO 65211, USA.
Carol A
CA
Deakyne
Department of Chemistry, University of Missouri, Columbia, MO 65211, USA. Electronic address: jurissons@missouri.edu.
Silvia S
SS
Jurisson
D000577:Amides / Q000737:chemistry*; D000588:Amines / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D008024:Ligands; D051379:Mice; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D012211:Rhenium / Q000737:chemistry*; D014018:Tissue Distribution; D014050:Toluene / Q000031:analogs & derivatives* / Q000737:chemistry
D000577:Amides; D000588:Amines; D002614:Chelating Agents; D008024:Ligands; D009942:Organometallic Compounds; D014050:Toluene; D012211:Rhenium; C004848:dithiol
Bombesin; MAMA ligands; Quantum chemical studies; Radiotherapy; Rhenium(V); Rhenium-186
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