A novel series of benzofuran derivatives as potential positron emission tomography (PET) tracers targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of benzofurans were successfully achieved by an intramolecular Wittig reaction between triphenylphosphonium salt and 4-nitrobenzoyl chloride. When in vitro binding studies using AD brain gray matter homogenates were carried out with a series of benzofuran derivatives, all the derivatives examined displayed high binding affinities with K(i) values in the subnanomolar range. Among these benzofuran derivatives, compound 8, 5-hydroxy-2-(4-methyaminophenyl)benzofuran, showed the lowest K(i) value (0.7 nM). In vitro fluorescent labeling of AD sections with compound 8 intensely stained not only amyloid plaques, but also neurofibrillary tangles. The (11)C labeled compound 8, [(11)C]8, was prepared by reacting the normethyl precursor, 5-hydroxy-2-(4-aminophenyl)benzofuran, with [(11)C]methyl triflate. The [(11)C]8 displayed moderate lipophilicity (log P = 2.36), very good brain penetration (4.8%ID/g at 2 min after iv injection in mice), and rapid washout from normal brains (0.4 and 0.2%ID/g at 30 and 60 min, respectively). In addition, this PET tracer showed in vivo amyloid plaque labeling in APP transgenic mice. Taken together, the data suggest that a relatively simple benzofuran derivative, [(11)C]8, may be a useful candidate PET tracer for detecting amyloid plaques in the brains of patients with Alzheimer's disease.

Previous studies on indium-111 (111In) labeling of polypeptides and peptides using cyclic diethylenetriaminepentaacetic dianhydride (cDTPA) as a bifunctional chelating agent (BCA) have indicated that DTPA might be a useful BCA for 111In labeling of polypeptides at high specific activities when DTPA can be incorporated without inducing intra- or intermolecular cross-linking. To investigate this hypothesis, a monoreactive DTPA derivative with a maleimide group as the peptide binding site (MDTPA) was designed and synthesized. A monoclonal antibody (OST7, IgG1) was used as a model polypeptide, and conjugation of MDTPA with OST7, 111In radiolabeling of MDTPA-OST7, and the stability of 111In-MDTPA-OST7 were investigated using cDTPA and benzyl-EDTA derivatives as references. SDS-PAGE analysis demonstrated that while cDTPA induced intramolecular cross-linking, no such undesirable side reactions were observed with MDTPA. MDTPA generated 111In-labeled OST7 with high radiochemical yields at higher specific activities than those produced using cDTPA and benzyl-EDTA derivatives as the BCAs. Incubation of each 111In-labeled OST7 in human serum indicated that MDTPA generated 111In-labeled OST7 of much higher and a little lower stability than those derived from cDTPA and benzyl-EDTA derivatives, respectively. These findings indicated that the low in vivo stability of cDTPA-conjugated antibody reported previously is not attributable to low stability of 111In-DTPA but to formation of intramolecular cross-linking during cDTPA conjugation reactions. The present study also indicated that MDTPA and its precursor, the tetra-tert-butyl derivative of DTPA, would be useful BCAs for 111In radiolabeling of polypeptides that have rapid blood clearance with high specific activities.

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Four 99mTc-labeled chalcone derivatives and their corresponding rhenium analogues were tested as potential probes for imaging β-amyloid plaques. The chalcones showed higher affinity for Aβ(1-42) aggregates than did 99m Tc complexes. In sections of brain tissue from an animal model of AD, the four Re chalcones intensely stained β-amyloid plaques. In biodistribution experiments using normal mice,

In vivo imaging of beta-amyloid (A beta) peptide aggregates in the brain may lead to early detection of Alzheimer's disease (AD) and monitoring of the progression and effectiveness of AD treatment. The purpose of this study was to develop novel amyloid imaging agents based on flavone as a core structure. Radioiodinated flavone derivatives were designed and synthesized. The binding affinities of flavone derivatives for A beta aggregates varied from 13 to 77 nM. When in vitro plaque labeling was carried out using post-mortem AD brain sections, all flavones intensely stained not only amyloid plaques but also cerebrovascular amyloids. In biodistribution studies using normal mice, they displayed high brain uptakes ranging from 3.2 to 4.1% ID/g at 2 min postinjection. The radioactivity washed out from the brain rapidly (0.5-1.9% ID/g at 30 min), which is highly desirable for amyloid imaging agents. The results in the study suggest that these classes of radioiodinated flavones may be useful candidates as potential imaging agents for amyloid plaques.

Reduction of radioactivity levels in nontarget tissues such as the liver and kidney constitutes a problem to be resolved in diagnostic and therapeutic applications of radiolabeled monoclonal antibodies (mAbs). A new radioiodination reagent with an ester bond to liberate m-iodohippuric acid from covalently conjugated proteins, maleimidoethyl 3-(tri-n-butylstannyl)hippurate (MIH), was recently developed. MIH liberated m-iodohippuric acid from galactosylneoglycoalbumin in murine liver, and the radiometabolite was rapidly eliminated from the liver into urine as an intact structure. In this study, intact IgG and Fab fragment of a mAb against osteogenic sarcoma were radioiodinated with MIH to further assess the applicability of MIH to radioimmunoimaging and therapy. For comparison, a mAb radioiodinated with N-succinimidyl iodobenzoate (SIB) and indium-111 (111In)-labeled mAbs with diethylenetriaminepentaacetic dianhydride (cDTPA) or 1-[4-[(5-maleimidopentyl)amino]benzyl]-ethylenediaminetetraacetic acid (EMCS-Bz-EDTA) were used. Size-exclusion HPLC analysis and cell binding assays indicated the preservation of both structure and antigen binding affinity of radioiodinated MIH-OST7 (IgG). In biodistribution studies in mice, [125I]MIH-OST7 (IgG) showed faster systemic clearance of radioactivity after 24 h postinjection than did [131I]SIB- and [111In]EMCS-Bz-EDTA-OST7 (IgG). [125I]MIH-OST7 (IgG) also exhibited much lower radioactivity levels in nontarget tissues such as the liver and kidney, with higher radioactivity levels in the blood up to 72 h postinjection when compared with [111In]cDTPA-OST7 (IgG). Radioactivity excreted from the mice was found in the urine as m-iodohippuric acid, following administration of [125I]MIH-OST7 (IgG). In athymic mice bearing osteogenic sarcoma, [131I]MIH-OST7 (IgG) indicated higher tumor-to-nontarget ratios of radioactivity at both 24 and 48 h postinjection than [125I]SIB-OST7 (IgG). Although both radioiodinated OST7s showed similar radioactivity levels in the target at 24 h postinjection, a small but significant decrease in the target radioactivity level was observed with [131I]MIH-OST7 (IgG) at 48 h postinjection. In addition, [131I]MIH-OST7 (Fab) showed very rapid cleavage of the ester bond both in vivo and in vitro. These findings indicated that while MIH may be a useful reagent for radioimmunoimaging using IgG, mAb, its application to smaller molecular weight mAbs and radioimmunotherapy would be hindered due to the labile characteristics of the ester bond in plasma. Thus, while the present study reinforced the usefulness of metabolizable linkages for reducing nontarget radioactivity levels, a development of plasma-stable metabolizable linkages is also warranted for radioimmunotherapy and for smaller molecular weight polypeptides.

It was found that the chelating resins (RNH) containing amidoxime groups show the selective adsorption ability for uranium in sea water. The favorable chelating resins were prepared by the reaction of macroreticular acryronitrile-divinylbenzene copolymer beads with hydroxylamine in methanol. When sea water (104 times as large as the resin volume) was passed through the RNH column at the space velocity of 60 hr-1, 80% of uranium on that in sea water was recovered. The elution of uranium adsorbed on RNH was accomplished by passing 1 N sulfuric acid solution through it. The recycle of adsorption and elution was found to be satisfactory.

This paper describes the synthesis and biological evaluation of fluoro-pegylated (FPEG) chalcones for the imaging of beta-amyloid (Abeta) plaques in patients with Alzheimer's disease (AD). FPEG chalcone derivatives were prepared by the aldol condensation reaction. In binding experiments conducted in vitro using Abeta(1-42) aggregates, the FPEG chalcone derivatives having a dimethylamino group showed higher Ki values (20-50 nM) than those having a monomethylamino or a primary amine group. When the biodistribution of 11C-labeled FPEG chalcone derivatives having a dimethyamino group was examined in normal mice, all four derivatives were found to display sufficient uptake for imaging Abeta plaques in the brain. 18F-labeled 7c also showed good uptake by and clearance from the brain, although a slight difference between the 11C and 18F tracers was observed. When the labeling of Abeta plaques was carried out using brain sections of AD model mice and an AD patient, the FPEG chalcone derivative 7c intensely labeled Abeta plaques. Taken together, the results suggest 7c to be a useful candidate PET tracer for detecting Abeta plaques in the brain of patients with AD.