TY - JOUR
T1 - 99mTc-labeled chemotactic peptides
T2 - Influence of coligand on distribution of molecular species and infection imaging properties. Synthesis and structural characterization of model complexes with the {Re(η2-HNNC5H4N)(η1-NNC5H4N)} core
AU - Babich, John W.
AU - Graham Coco, Wendy
AU - Barrow, Sandra
AU - Fischman, Alan J.
AU - Femia, Frank J.
AU - Zubieta, Jon
N1 - Funding Information:
This work was supported by a grant from the Department of Energy (DOE), Office of Health and Environmental Research D2-FG02-99ER62791.
PY - 2000/11/20
Y1 - 2000/11/20
N2 - 99mTc-labeled hydrazino nicotinamide (HYNIC) derivatized chemotactic peptides are useful infection imaging agents. However, the reagent that is used for radiolabeling ('coligand') can have profound effects on biodistribution. In this study, the distribution of molecular species formed with a variety of coligands was correlated with infection localization and biodistribution in E. coli infected rabbits. Five 99mTc-coligand complexes (mannitol, glucamine, glucarate, tricine and glucoheptonate) were used to label f-MLFK-HYNIC and radiolabeled species were characterized by reverse phase HPLC. One mCi of each 99mTc-coligand-peptide complex was injected into rabbits 24 h after infection and imaging was performed 3-4 and 16-17 h later. After acquiring the final images, the animals were euthanized and biodistribution was measured. With all five coligands, 99mTc-labeled peptide was obtained in > 90% radiochemical purity. Multiple radiolabeled species were obtained with each reagent; however, mannitol yielded the most homogeneous product. Model studies on the robust {Re(η2-HNNC5H4N)(η1-NNC5H4)} core demonstrate that ligands such as mannitol, tricine, tris(hydroxymethyl)propane, glucarate-a, glucarate-b, and glucoheptonate yield intractable mixtures of products as a consequence of the ambidentate nature of these ligands and their facile displacement by other donor groups, including solvent molecules. In contrast, dihydroxylic ligands with an additional imine functionality and a meridional geometric preference yield monophasic materials upon reaction with [ReCl3(η1-NNC5H4NH)(η2-HNNC5H4N)]. Both [Re{η3-C5H3N-2,6-(CH2O)2}(η1-NNC5H4N)(η2-HNNC5H4N)] (1) and [Re{η3-OC6H4C(H)=NC6H40}(η1-NNC5H4N)(η2-HNNC5H4N)] (2) exhibit distorted octahedral geometries with a meridional disposition of the bidentate pyridinediazene and pyridinediazenido(1-) ligands and the three remaining meridional positions occupied by the two oxygen and the nitrogen donors of the tridentate coligand. Image analysis demonstrated that 99mTc-mannitol-f-MLFK-HYNIC produced the highest target to background ratios (T/B). The T/B values were: 3.91 ± 0.99, 6.15 ± 1.07, 2.8 ± 1.07, 2.57 ± 1.07, 3.41 ± 1.07 and 1.8 ± 1.07 at 3-4 h and 11.9 ± 0.99, 3.94 ± 1.07, 3.79 ± 1.07, 4.81 ± 1.17, 7.0 ± 1.31 and 5.32 ± 1.07 at 16-17 h for mannitol, tricine, glucamine, glucarate-a, glucarate-b, and glucoheptonate, respectively. At both imaging times, 99mTc-mannitol-f-MLFK-HYNIC had the lowest relative levels of accumulation in bowel. Biodistribution measurements demonstrated that the mannitol preparation had the highest level of accumulation (%ID g-1) in infected tissue; mannitol > glucoheptonate = glucarate-b > glucarate-a > glucamine > tricine; P < 0.01. The infected to normal muscle ratio for 99mTc-mannitol-f-MLFK-HYNIC was ~ 50:1. These results support our previous findings in rats that coligands can markedly effect the biodistribution and infection localization of 99mTc-labeled HYNIC chemotactic peptides. For infection imaging, the mannitol preparation had the most favorable combination of accumulation in infected tissue, T/B ratio and biodistribution in uninfected organs. (C) 2000 Elsevier Science B.V.
AB - 99mTc-labeled hydrazino nicotinamide (HYNIC) derivatized chemotactic peptides are useful infection imaging agents. However, the reagent that is used for radiolabeling ('coligand') can have profound effects on biodistribution. In this study, the distribution of molecular species formed with a variety of coligands was correlated with infection localization and biodistribution in E. coli infected rabbits. Five 99mTc-coligand complexes (mannitol, glucamine, glucarate, tricine and glucoheptonate) were used to label f-MLFK-HYNIC and radiolabeled species were characterized by reverse phase HPLC. One mCi of each 99mTc-coligand-peptide complex was injected into rabbits 24 h after infection and imaging was performed 3-4 and 16-17 h later. After acquiring the final images, the animals were euthanized and biodistribution was measured. With all five coligands, 99mTc-labeled peptide was obtained in > 90% radiochemical purity. Multiple radiolabeled species were obtained with each reagent; however, mannitol yielded the most homogeneous product. Model studies on the robust {Re(η2-HNNC5H4N)(η1-NNC5H4)} core demonstrate that ligands such as mannitol, tricine, tris(hydroxymethyl)propane, glucarate-a, glucarate-b, and glucoheptonate yield intractable mixtures of products as a consequence of the ambidentate nature of these ligands and their facile displacement by other donor groups, including solvent molecules. In contrast, dihydroxylic ligands with an additional imine functionality and a meridional geometric preference yield monophasic materials upon reaction with [ReCl3(η1-NNC5H4NH)(η2-HNNC5H4N)]. Both [Re{η3-C5H3N-2,6-(CH2O)2}(η1-NNC5H4N)(η2-HNNC5H4N)] (1) and [Re{η3-OC6H4C(H)=NC6H40}(η1-NNC5H4N)(η2-HNNC5H4N)] (2) exhibit distorted octahedral geometries with a meridional disposition of the bidentate pyridinediazene and pyridinediazenido(1-) ligands and the three remaining meridional positions occupied by the two oxygen and the nitrogen donors of the tridentate coligand. Image analysis demonstrated that 99mTc-mannitol-f-MLFK-HYNIC produced the highest target to background ratios (T/B). The T/B values were: 3.91 ± 0.99, 6.15 ± 1.07, 2.8 ± 1.07, 2.57 ± 1.07, 3.41 ± 1.07 and 1.8 ± 1.07 at 3-4 h and 11.9 ± 0.99, 3.94 ± 1.07, 3.79 ± 1.07, 4.81 ± 1.17, 7.0 ± 1.31 and 5.32 ± 1.07 at 16-17 h for mannitol, tricine, glucamine, glucarate-a, glucarate-b, and glucoheptonate, respectively. At both imaging times, 99mTc-mannitol-f-MLFK-HYNIC had the lowest relative levels of accumulation in bowel. Biodistribution measurements demonstrated that the mannitol preparation had the highest level of accumulation (%ID g-1) in infected tissue; mannitol > glucoheptonate = glucarate-b > glucarate-a > glucamine > tricine; P < 0.01. The infected to normal muscle ratio for 99mTc-mannitol-f-MLFK-HYNIC was ~ 50:1. These results support our previous findings in rats that coligands can markedly effect the biodistribution and infection localization of 99mTc-labeled HYNIC chemotactic peptides. For infection imaging, the mannitol preparation had the most favorable combination of accumulation in infected tissue, T/B ratio and biodistribution in uninfected organs. (C) 2000 Elsevier Science B.V.
KW - Reverse-phase HPLC
KW - Rhenium complexes
KW - Tc-coligand complexes
KW - Tc-labeled chemotactic peptides
KW - Tc-labeled hydrazino nicotinamide
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U2 - 10.1016/S0020-1693(00)00255-3
DO - 10.1016/S0020-1693(00)00255-3
M3 - Article
AN - SCOPUS:0034693831
SN - 0020-1693
VL - 309
SP - 123
EP - 136
JO - Inorganica Chimica Acta
JF - Inorganica Chimica Acta
IS - 1-2
ER -