Search

Abstract: KR-31831 ((2R,3R,4S)-6-amino-4-[N-(4-chloropheyl)-N-(1H-imidazol-2ylmethyl)amino]-3-hydroxyl-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran), an angiogenesis inhibitor, was evaluated in tumor-bearing mice using molecular imaging technology. Pre-treatment microPET images were acquired on SKOV-3 cell-implanted nude mice after injection with 64Cu-DOTA-VEGF121. KR-31831 (50 mg/kg) was then injected intraperitoneally into the treatment group (n=3), while injection vehicle was injected into the control (n=4) and blocking (n=3) groups. After injections occurred daily for 28 days, all groups of mice underwent post-treatment microPET imaging after injection with 64Cu-DOTA-VEGF121. The post-treatment images showed high tumor uptake in the control group and reduced tumor uptake in both the blocking and treatment groups. ROI analysis of the tumor images revealed 6.25%±1.18% ID/g at 1 h, 6.55%±0.69% ID/g at 2 h, and 4.68%±0.63% ID/g at 16 h in the control group; 3.87%±0.45% ID/g at 1 h, 4.50%±0.44% ID/g at 2 h, and 3.63%±0.25% ID/g at 16 h in the blocking group; and 4.03%±0.74% ID/g at 1 h, 4.37%±0.67% ID/g at 2 h, and 3.83%±0.90% ID/g at 16 h in the treatment group. Biodistribution obtained after the post-treatment microPET imaging also demonstrated high tumor uptake (3.74%±0.27% ID/g) in the control group and reduced uptakes in both the blocking group (2.69%±0.73% ID/g, P<.05) and the treatment group (3.11%±0.25% ID/g, P<.05), which correlated well with microPET imaging data. Immunofluorescence analysis showed higher levels of VEGFR2 and CD31 expressions in tumor tissues of the control and blocking groups than in tumor tissues of the treatment group. These results suggest that the antiangiogenic activity of KR-31831 is mediated through VEGFR2 and microPET serves as a useful molecular imaging tool for evaluation of a newly developed angiogenesis inhibitor, KR-31831. [Copyright &y& Elsevier]

In the present study, a styryltriazole and four resveratrolderivativeswere synthesized as candidates for β-amyloid (Aβ) plaqueimaging. On the basis of their binding affinities to Aβ(1–42)aggregates, the styryltriazole (1, Ki= 12.8 nM) and one resveratrol derivative (5, Ki= 0.49 nM) were labeled with 18F. In normal mice, tissue distribution of [18F]5showed good initial brain uptake (3.26% ID/g at 2 min) butslow wash-out from brains (2-to-60 min uptake ratio: 2.9). Furthermore,it underwent in vivo metabolic defluorination (1.88% ID/g at 2 min and 9.73% ID/g at 60 min). In contrast, [18F]1displayedhigh initial brain uptake (5.38% ID/g at 2 min) with rapid wash-outfrom brains (0.52% ID/g at 60 min; 2-to-60 min uptake ratio: 10.3).These results indicate that [18F]1has invivo kinetics comparable to PET radiopharmaceuticals currently undercommercial development, demonstrating that [18F]1is a desirable PET radioligand for Aβ plaque imaging. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer’s disease is characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. We previously developed [18F]fluoropropylcurcumin ([18F]FP-curcumin), which demonstrated excellent binding affinity (Ki =0.07nM) for Aβ(1–40) aggregates and good pharmacokinetics in normal mouse brains. However, its initial brain uptake was poor (0.52% ID/g at 2min post-injection). Therefore, in the present study, fluorine-substituted 4,4′-bissubstituted or pegylated curcumin derivatives were synthesized and evaluated. Their binding affinities for Aβ(1–42) aggregates were measured and 1-(4-fluoroethyl)-7-(4′-methyl)curcumin (1) had the highest binding affinity (Ki =2.12nM). Fluorescence staining of Tg APP/PS-1 mouse brain sections demonstrated high and specific labeling of Aβ plaques by 1 in the cortex region, which was confirmed with thioflavin-S staining of the same spots in the adjacent brain sections. Radioligand [18F]1 was found to have an appropriate partition coefficient (log P o/w =2.40), and its tissue distribution in normal mice demonstrated improved brain permeability (1.44% ID/g at 2min post-injection) compared to that of [18F]FP-curcumin by a factor of 2.8 and fast wash-out from mouse brains (0.45% ID/g at 30min post-injection). These results suggest that [18F]1 may hold promise as a PET radioligand for Aβ plaque imaging. [Copyright &y& Elsevier]

Abstract: 2-Methoxyestradiol (1) is an endogenous metabolite of estradiol that has been shown to inhibit cell proliferation and angiogenesis. In this study, 2-[methyl-11C]methoxyestradiol ([11C]1) was synthesized and evaluated for in vivo studies on angiogenesis. Radiotracer [11C]1 was synthesized at a decay-corrected radiochemical yield of 25–34% from [11C]CH3I with a specific activity of 34–38 GBq/μmol. In vitro human umbilical vein endothelial cell uptake studies demonstrated that [11C]1 uptake increased time-dependently and that this uptake was inhibited by 70% in the presence of Compound 1, indicating its specific binding to cells. Tissue distribution in mice implanted with Lewis lung carcinoma cells showed high radioactivity accumulation in the liver, lungs and kidneys, and a tumor-to-muscle uptake ratio of 2.36. Pharmacokinetic analysis in mice intravenously injected with [11C]1 demonstrated a t 1/2α of 0.36 min, a t 1/2β of 19 min, a clearance of 0.36 ml/min and a volume of distribution of 52.9 ml. In addition, Compound 1 showed linear pharmacokinetics at dose levels between 0.14 and 8.5 μg in mice. Taken together, [11C]1 may be useful for in vivo studies on angiogenesis. [Copyright &y& Elsevier]