ABSTRACT
We report the synthesis and evaluation of a series of N-benzoylindole derivatives as novel potential imaging agents for ß-amyloid plaques. In vitro binding studies using Aß(1-40) aggregates versus [(125)I]TZDM showed that all these derivatives demonstrated high binding affinities (K(i) values ranged from 8.4 to 121.6 nM). Moreover, two radioiodinated compounds [(125)I]7 and [(125)I]14 were prepared. Autoradiography for [(125)I]14 displayed intense and specific labeling of Aß plaques in the brain sections of AD model mice (C57, APP/PS1) with low background. In vivo biodistribution in normal mice exhibited sufficient initial brain uptake for imaging (2.19% and 2.00%ID/g at 2 min postinjection for [(125)I]7 and [(125)I]14, respectively). Although additional modifications are necessary to improve brain uptake and clearance from the brain, the N-benzoylindole may be served as a backbone structure to develop novel ß-amyloid imaging probes.
Subject(s)
Amyloid beta-Peptides/metabolism , Indoles/pharmacokinetics , Molecular Probes/pharmacokinetics , Plaque, Amyloid/metabolism , Animals , Brain/metabolism , Dose-Response Relationship, Drug , Indoles/chemistry , Indoles/metabolism , Male , Mice , Mice, Inbred C57BL , Molecular Probes/chemistry , Molecular Probes/metabolism , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Tissue DistributionABSTRACT
A group of novel 4,5-dianilinophthalimide derivatives has been synthesized in this study for potential use as beta-amyloid (Abeta) plaque probes. Staining of hippocampus tissue sections from Alzheimer's disease (AD) brain with the representative compound 9 indicated selective labeling of it to Abeta plaques. The binding affinity of radioiodinated [(125)I]9 for AD brain homogenates was 0.21 nM (K(d)), and of other derivatives ranged from 0.9 to 19.7 nM, except for N-methyl-4,5-dianilinophthalimide (K(i)>1000 nM). [(125)I]9 possessed the optimal lipophilicity with LogP value of 2.16, and its in vivo biodistribution in normal mice exhibited excellent initial brain uptake (5.16% ID/g at 2 min after injection) and a fast washout rate (0.56% ID/g at 60 min). The encouraging results suggest that this novel derivative of [(123)I]9 may have potential as an in vivo SPECT probe for detecting amyloid plaques in the brain.
Subject(s)
Alzheimer Disease/diagnostic imaging , Amyloid beta-Peptides/metabolism , Aniline Compounds , Brain/diagnostic imaging , Phthalimides , Tomography, Emission-Computed, Single-Photon/methods , Aniline Compounds/chemistry , Animals , Brain/metabolism , Brain/pathology , Humans , Mice , Phthalimides/chemistryABSTRACT
Two novel [99mTc] [ SNN/S] "3+1" mixed ligand complexes, where L3H2= o-methylthio-glycinanilide (A) or N-(1-methylthio-phenyl)-ethylenediamine (B) and L1H= isopropanethiol, were synthesized using stannous chloride as reductant and glucoheptonate as transfer ligand. The identifications of [99mTc]-A and [99mTc]-B were established by thin layer chromatography. The radiochemical purity of both complexes was over 90%. The initial biodistribution study in mice demonstrated that both complexes can penetrate the intact blood-brain barrier and exhibit retention in mice brain. The brain uptake (%ID/g) values of [99mTc]-A were 1.68, 1.23, 1.24 and of [99mTc]-B were 1.76, 1.08, 0.90 at 2, 30 and 60 min i.v. postinjection, respectively.
