Early Detection of Aß Deposition in the 5xFAD Mouse by Amyloid PET.

Purpose.18F-FC119S is a positron emission tomography (PET) tracer for imaging ß-amyloid (Aß) plaques in Alzheimer's disease (AD). The aim of this study is to evaluate the efficacy of 18F-FC119S in quantitating Aß deposition in a mouse model of early amyloid deposition (5xFAD) by PET. Method. Dynamic 18F-FC119S PET images were obtained in 5xFAD (n = 5) and wild-type (WT) mice (n = 7). The brain PET images were spatially normalized to the M. Mirrione T2-weighted mouse brain MR template, and the volumes of interest were then automatically drawn on the cortex, hippocampus, thalamus, and cerebellum. The specific binding of 18F-FC119S to Aß was quantified as the distribution volume ratio using Logan graphical analysis with the cerebellum as a reference tissue. The Aß levels in the brain were also confirmed by immunohistochemical analysis. Result. For the 5xFAD group, radioactivity levels in the cortex, the hippocampus, and the thalamus were higher than those for the WT group. In these regions, specific binding was approximately 1.2-fold higher in 5xFAD mice than in WT. Immunohistochemistry supported these findings; the 5xFAD showed severe Aß deposition in the cortex and hippocampus in contrast to the WT group. Conclusion. These results demonstrated that 18F-FC119S PET can successfully distinguish Aß depositions in 5xFAD mice from WT.

Synthesis and evaluation of a 18F-labeled 4-ipomeanol as an imaging agent for CYP4B1 gene prodrug activation therapy.

We report the development of a (18)F-labeled 4-ipomeanol (4-IM), which is metabolized by the CYP4B1 enzyme, to image tumors and monitor enzyme-activating anticancer prodrugs. The fluorine-substituted derivative, 1-(3-furyl)-4-hydroxy-5-fluoro-1-pentanone (F-4-IM, 1), was synthesized from 3-furaldehyde. [(18)F]F-4-IM ([(18)F]1) was prepared in 20%-35% radiochemical yield by a fluorine-18 displacement reaction, followed by reduction and deprotection of the ketal group, and was shown to be stable (>96% at 2 hours) in human serum at 37°C. The biodistribution of [(18)F]F-4-IM in normal rats was high in the lung, where CYP4B1 gene is preferentially expressed. We transduced C6-glioma cells with a retrovirus-expressing CYP4B1 (C6-CYP4B1). Evaluation of CYP4B1 expression was confirmed by reverse transcription polymerase chain reaction and MTT assay. Cell assays were carried out using C6 and C6-CYP4B, and the uptake of [(18)F]F-4-IM in these cells was compared with that in parental controls. The uptake ratio of [(18)F]F-4-IM was 2.8-fold higher in C6-CYP4B1 compared with that in parental cells at 1 hour, whereas [(3)H]4-IM was taken up at similar rates in both cell lines after 6 hours. These results suggest that [(18)F]F-4-IM could be a promising PET imaging agent with potential to be used for imaging of CYP4B1-transfected tumor cells, as well as for monitoring CYP4B1 enzyme/prodrug interactions.

Synthesis of novel phytosphingosine derivatives and their preliminary biological evaluation for enhancing radiation therapy.

Eight d-ribo-phytosphingosine derivatives were synthesized from d-ribo-phytosphingosine and diverse acyl chlorides with N,N-diisopropylethylamine in tetrahydrofuran for 1h at room temperature. Effect of these compounds on IR-induced cell death was evaluated on blood cancer cells (Jurkat). Among these, 3d showed the highest enhancement of radiosensitizing effect.

Fully automated synthesis of [18F]fluoromisonidazole using a conventional [18F]FDG module.

We developed a new fully automated method for the synthesis of [18F]fluoromisonidazole ([18F]FMISO) by modifying a commercial FDG synthesizer and its disposable fluid pathway. A three-step procedure was used to prepare the tosylate precursor, 1-(2'-nitro-1'-imidazolyl)-2-O-tetrahydrofuranyl-3-O-toluenesulfonylpropanediol. Using glycerol as the starting material, the precursor was synthesized with a yield of 21%. The optimal labeling conditions for the automated synthesis of [18F]FMISO was 10 mg of precursor in acetonitrile (2 ml heated at 105 degrees C for 360 s, followed by heating at 75 degrees C for 280 s and hydrolysis with 1 N HCl at 105 degrees C for 300 s. Using 3.7 GBq of [18F]F- as a starting activity, [18F]FMISO was obtained with high end-of-synthesis (EOS) radiochemical yields of 58.5+/-3.5% for 60.0+/-5.2 min with high-performance liquid chromatography (HPLC) purification. When solid-phase purification steps were added, the EOS radiochemical yields were 54.5+/-2.8% (337+/-25 GBq/micromol) for 70.0+/-3.8 min (n=10 for each group, decay-corrected). With a high starting radioactivity of 37.0 GBq, we obtained radiochemical yields of 54.4+/-2.9% and 52.8+/-4.2%, respectively (n=3). The solid-phase purification removed unreacted [18F]fluoride and polar impurities before the HPLC procedure. Long-term tests showed a good stability of 98.2+/-1.5%. This new automated synthesis procedure combines high and reproducible yields with the advantage of using a disposable cassette system.

Synthesis and evaluation of fluorine-substituted 1H-pyrrolo[2,3-b]pyridine derivatives for dopamine D4 receptor imaging.

Seven fluorine-substituted 1H-pyrrolo[2,3-b]pyridine derivatives were synthesized based on a lead ligand, 3-[[4-(4-iodophenyl)piperazin-1-yl]-methyl]-1H-pyrrolo[2,3-b]pyridine (L-750,667) and evaluated as potential dopamine D(4) receptor imaging agents by positron emission tomography (PET). Binding affinities of these ligands for the dopamine D(2), D(3), and D(4) receptor subtypes were measured in vitro. Most ligands showed high and selective binding for the D(4) receptor. Ligand 7 had high affinity for the D(4) receptor, whereas ligands 1, 2, and 6 showed high selectivity for the D(4) receptor. LogP values were calculated for the ligands in this series and ligand 6 had the lowest lipophilicity. (18)F-labeled ligand 7 demonstrated a uniform regional brain distribution and a rapid washout in mice, probably due to nonspecific binding. Based on their in vitro binding properties and calculated logP values, ligand 6 appears to have the most promise for dopamine D(4) receptor imaging.

Synthesis of radioiodine labeled dibenzyl disulfide for evaluation of tumor cell uptake.

Benzyl 4-halobenzyl and ally benzyl disulfide were synthesized as diallyl disulfide analogues and their tumor growth inhibitory effects on the cancer cells (SNU C5 and MCF-7) were comparable to that of diallyl disulfide, indicating that the disulfide functional group was responsible for the tumor growth inhibitory effects. Cu(I)-assisted radioiodination of benzyl 4-bromobenzyl disulfide gave benzyl 4-[123I/125I]iodobenzyl disulfide in 30-40% radiochemical yield. The radiolabeled disulfide was taken up by the cancer cells in a time-dependent manner, and the uptake was inhibited by the pretreatment of S-methyl methanethiosulfonate (MMTS), phorone and diallyl disulfide. This study suggested that the radiolabeled dibenzyl disulfide was taken up by the cancer cells via thiol-disulfide exchange and retained inside the cells.