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Purpose 4-(3S)-3-[5-(2-[18F]-fluoroethoxy)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]-piperidin-3-yl}carbonyl)amino]propanoic acid ([18F]GP1) is a radiotracer developed for targeted imaging of activated platelet glycoprotein IIb/IIIa receptors with positron emission tomography/computed tomography (PET/CT) in acute thromboembolism. We evaluated here radiation dosimetry of [18F]GP1 in humans. Procedures We studied 30 subjects (10 with deep vein thrombosis, 10 with pulmonary embolism, and 10 with arterial thromboembolism) who had signs or symptoms of acute thromboembolism, and were confirmed to have thromboembolic foci by imaging studies. Dynamic whole-body PET/CT images were acquired for up to 140 min after injection of 250 MBq of [18F]GP1. Radiation absorbed dose and effective dose were calculated using the OLINDA/EXM software. Results [18F]GP1 PET images showed high initial uptake of the tracer in the heart, spleen, kidney, and liver. [18F]GP1 activity was cleared by hepatobiliary and urinary excretion. The organ receiving the highest radiation absorbed dose (mGy/MBq) was the urinary bladder (0.0884 ± 0.0458), followed by upper large intestine (0.0498 ± 0.0189), small intestine (0.0454 ± 0.0166), and kidneys (0.0350 ± 0.0231). The effective dose (mSv/MBq) was 0.0212 ± 0.0027 (ICRP 103). ED was not significantly different between the three disease groups (p = 0.94). A 45-minute voiding reduced the urinary bladder wall radiation dose to 0.0495 ± 0.0140 mGy/MBq, and effective dose (ICRP 103) to 0.0186 ± 0.0030. Conclusions [18F]GP1 has favorable radiation dosimetry profile for clinical PET/CT imaging. The ED is comparable to commonly used 18F PET tracers.

Summary Background A biopsy of first recurrence or metastatic disease is recommended to re-evaluate oestrogen receptor status in patients with breast cancer and to select appropriate treatment. However, retesting for oestrogen receptor status with rebiopsy is not always feasible, depending on lesion location and the risk associated with biopsy, and in these cases clinicians continue to treat patients according to the oestrogen receptor status of the primary tumour. Consequently suboptimal therapy might be offered to these patients. We assessed the diagnostic accuracy and safety of 16α-[18F]fluoro-17β-oestradiol (18F-FES) PET-CT to assess oestrogen receptor status in patients with recurrent or metastatic breast cancer. Methods We did a prospective cohort study at the Asan Medical Center, Seoul, South Korea. Eligible patients had breast cancer, with first recurrence or metastatic disease at presentation, were 19 years or older, and had an Eastern Cooperative Oncology Group performance status of 0–2. The primary objective was to show the agreement between qualitative 18F-FES PET-CT interpretation and the results of oestrogen receptor expression by immunohistochemical assay, a non-reference standard test. Whole-body 18F-FES PET-CT imaging was done after intravenous injection of 111–222 MBq of 18F-FES, with dosing primarily determined by radiation dosimetry analysis. 18F-FES uptake above background intensity was interpreted as positive. Efficacy was assessed in all patients with histologically confirmed recurrent or metastatic breast cancer who received 18F-FES and had PET-CT images available (intention-to-diagnose analysis), and safety was assessed in all patients who received 18F-FES. This study is registered with ClinicalTrials.gov, number NCT01986569. Findings Between Nov 27, 2013, and Nov 10, 2016, 93 patients were enrolled. Of the 85 patients included in the efficacy analysis, 47 (55%) were oestrogen receptor-positive and 38 (45%) were oestrogen receptor-negative. Positive status percent agreement between the 18F-FES PET-CT results and oestrogen receptor status by immunohistochemical assay was 76·6% (95% CI 62·0–87·7) and the negative status percent agreement was 100·0% (90·8–100·0). Patients who were oestrogen receptor-positive and had a positive 18F-FES PET-CT result had a significantly higher progesterone receptor expression than those who were oestrogen receptor-positive and had a negative 18F-FES PET-CT result (23 [68%] of 34 patients vs 0 of 11 patients; p Interpretation The high negative percent agreement between 18F-FES PET-CT and oestrogen receptor status by immunohistochemical assay in this cohort suggests that positive 18F-FES uptake by recurrent or metastatic oestrogen receptor-positive breast cancer lesions could be an alternative to oestrogen receptor assays in this setting. Staging assessment should include 18F-FES PET-CT when retesting oestrogen receptor status is not feasible. Funding Asan Institute for Life Sciences, Ministry of Health and Welfare, South Korea.

Graphene quantum dots-based nanoparticles (GQD-NPs) with reduction-responsive properties were synthesized via conjugation with two precursors, doxorubicin-disulfide-GQD that endowed the drug loading capability and polyethylene glycol-disulfide-Herceptin that enhanced the half-life and conferred active targeting ability towards HER2-overexpressed cancer. Disulfide linkages between the compartments are cleaved at a physiologically relevant concentration of glutathione in cancer cells, resulting a controlled release of drugs. In vitro analysis confirmed successful internalization of GQD-NPs in the cytoplasm and enhanced cellular uptake of DOX in HER2-positive breast cancer cells. The GQD-NPs show potential as a theranostic agent for HER2-overexpressed breast cancer cells.

The concept of cognitive reserve (CR) originated from discrepancies between the degree of brain pathology and the severity of clinical manifestations. CR has been characterized through CR proxies, such as education and occupation complexity; however, such approaches have inherent limitations. Although several methods have been developed to overcome these limitations, they fail to reflect the entire Alzheimer's disease (AD) pathology. Meanwhile, graph theory analysis, one of most powerful and flexible approaches, have established remarkable network properties of the brain. The functional and structural brain networks are damaged in neurodegenerative diseases. Therefore, network analysis has been applied to clarify the characteristics of the disease or give insight. Here, using multimodal neuroimaging, we propose an intuitive model to estimate CR based on its original definition, and explore the neural substrates of CR from the perspective of networks and functional connectivity. A total of 87 subjects (21 AD, 32 mild cognitive impairment, and 34 normal aging) underwent tau and amyloid PET, 3D T1-weighted MR, and resting-state fMRI. We hypothesized CR as a residual of actual cognitive performance and expected performance to be related to quantitative factors, such as AD pathology, demographics, and a genetic factor. Then, we correlated this marker using education and occupation complexity as conventional CR proxies. We validated this marker by testing whether it would modulate the effect of brain pathology on memory function. To examine the neural substrates associated with CR, we performed graph analysis to investigate the association between the CR marker and network measures at different granularities in total subjects, AD spectrum and normal aging, respectively. The CR marker from our model was well associated with education and occupation complexity. More directly, the CR marker was revealed to modify the relationship between brain pathology and memory function among AD spectrum. The CR marker was correlated with the global efficiency of the entire network, nodal clustering coefficient, and local efficiency of the right middle-temporal pole. In connectivity analysis, one cluster of edges centered on right middle-temporal pole was significantly correlated with the CR marker. In subgroup analysis, the network measures of right middle-temporal pole still correlated with the CR marker among AD spectrum. However, right precentral gyrus was revealed to be associated with the CR marker in normal aging. This study demonstrates that our intuitive model using multimodal neuroimaging and network perspective adequately and comprehensively captures CR. From a network perspective, CR is associated with the capacity to process information efficiently in the brain. The right middle-temporal pole was revealed to be a pivotal neural substrate of CR in AD spectrum. These findings foster understanding of AD and will be useful to help identify individuals with vulnerability or resistance to AD pathology, and characterize patients for intervention or drug trials.

Since the foodborne pathogenic bacteria cause serious diseases and socio-economic losses throughout the world, the molecular diagnosis of foodborne poisoning pathogen in the early stage is essential for preventing excessive damages. In this study, a colorimetric based foodborne pathogen detection on the centrifugal microdevice was demonstrated in a high throughput manner. The developed centrifugal microdevice consists of a sample reservoir, a spiral shaped sample injection microchannel, 24 aliqouting chambers (2.5 μL each), cross capillary valves, and 24 reaction chambers on a single device. Once the sample was loaded, the rotation speed at 850 rpm allowed the sample solution to be divided into 24 aliqouting chambers. Then, the samples loaded in the aliqouting chambers could be injected into the reaction chambers at 5000 rpm evenly. The centrifugal device was placed in an oven at 66 °C for target gene amplification. As a gene amplification method, loop mediated isothermal amplification (LAMP) was used in which specific primer sets targeting three kinds of foodborne pathogens (Escherichia coli O157:H7, Salmonella typhimurium, and Vibrio parahaemolyticus) were included. The presence of each pathogen was identified by Eriochrome Black T (EBT)-mediated colorimetric change from purple to sky blue with the naked eye, and the color of each reaction chamber was analyzed by a ratiometric image processing method. Green/Red (G/R) and Blue/Red (B/R) ratios were set as the criteria to differentiate negative results from positive ones. The threshold values for G/R (0.915

Point-of-care (POC) molecular diagnostics plays a pivotal role for the prevention and treatment of infectious diseases. In spite of recent advancement in microfluidic based POC devices, there are still rooms for development to realize rapid, automatic and cost-effective sample-to-result genetic analysis. In this study, we propose an integrated rotary microfluidic system that is capable of performing glass microbead based DNA extraction, loop mediated isothermal amplification (LAMP), and colorimetric lateral flow strip based detection in a sequential manner with an optimized microfluidic design and a rotational speed control. Rotation direction-dependent coriolis force and siphon valving structures enable us to perform the fluidic control and metering, and the use of the lateral flow strip as a detection method renders all the analytical processes for nucleic acid test simplified and integrated without the need of expensive instruments or human intervention. As a proof of concept for point-of-care DNA diagnostics, we identified the food-borne bacterial pathogen which was contaminated in water or milk. Not only monoplex Salmonella Typhimurium but also multiplex Salmonella Typhimurium and Vibrio parahaemolyticus were analysed on the integrated rotary genetic analysis microsystem with a limit of detection of 50 CFU in 80min. In addition, three multiple samples were simultaneously analysed on a single device. The sample-to-result capability of the proposed microdevice provides great usefulness in the fields of clinical diagnostics, food safety and environment monitoring.

Resistance to DNA-damaging agents is one of the main reasons for the low survival of cervical cancer patients. Previous reports have suggested that the Cdc25A oncoprotein significantly affects the level of susceptibility to DNA-damaging agents, but the molecular mechanism remains unclear. In this study, we used Western blot and flow cytometry analyses to demonstrate that the deubiquitinating enzyme HAUSP stabilizes Cdc25A protein level. Furthermore, in a co-immunoprecipitation assay, we found that HAUSP interacts with and deubiquitinates Cdc25A both exogenously and endogenously. HAUSP extends the half-life of the Cdc25A protein by circumventing turnover. HAUSP knockout in HeLa cells using the CRISPR/Cas9 system caused a significant delay in Cdc25A-mediated cell cycle progression, cell migration, and colony formation and attenuated tumor progression in a mouse xenograft model. Furthermore, HAUSP-mediated stabilization of the Cdc25A protein produced enhanced resistance to DNA-damaging agents. Overall, our study suggests that targeting Cdc25A and HAUSP could be a promising combinatorial approach to halt progression and minimize antineoplastic resistance in cervical cancer.

We present a centrifugal microfluidic device which enables multiplex foodborne pathogen identification by loop-mediated isothermal amplification (LAMP) and colorimetric detection using Eriochrome Black T (EBT). Five identical structures were designed in the centrifugal microfluidic system to perform the genetic analysis of 25 pathogen samples in a high-throughput manner. The sequential loading and aliquoting of the LAMP cocktail, the primer mixtures, and the DNA sample solutions were accomplished by the optimized zigzag-shaped microchannels and RPM control. We targeted three kinds of pathogenic bacteria (Escherichia coli O157:H7, Salmonella typhimurium and Vibrio parahaemolyticus) and detected the amplicons of the LAMP reaction by the EBT-mediated colorimetric method. For the limit-of-detection (LOD) test, we carried out the LAMP reaction on a chip with serially diluted DNA templates of E. coli O157:H7, and could observe the color change with 380 copies. The used primer sets in the LAMP reaction were specific only to the genomic DNA of E. coli O157:H7, enabling the on-chip selective, sensitive, and high-throughput pathogen identification with the naked eyes. The entire process was completed in 60min. Since the proposed microsystem does not require any bulky and expensive instrumentation for end-point detection, our microdevice would be adequate for point-of-care (POC) testing with high simplicity and high speed, providing an advanced genetic analysis microsystem for foodborne pathogen detection.

An advanced centrifugal microsystem is developed which has capability of automatic and programmed chemical reagent loading and reactions to screen the colloidal nanocrystal synthesis in a high-throughput manner. As a proof of concept, triplicate synthetic reactions for water-soluble multi-color CdS nanocrystals are executed under ten different conditions on a chip. The proposed disk-shaped microdevice contains a top layer for distributing the reagents through zig-zag continuous channels and a bottom layer for 30 functional units, each of which is composed of a reaction chamber and three reservoirs connected with a control, a precursor, and a basic solution, respectively. All the reservoirs are linked to the main channel via different microfluidic channel dimension, and the main channel is directed to the reaction chamber. Through rotational speed control, the three solutions are sequentially loaded to the reaction chamber with precise volume, and the multiplex CdS nanocrystals synthesis is processed. By tuning the concentration of sulfur in a control solution, multi-color CdS nanocrystals are produced from green to red depending on the molar ratios of Cd2+ to S2−.

Cerebrovascular disease (CVD) and amyloid burden are the most frequent pathologies in subjects with cognitive impairment. However, the relationship between CVD, amyloid burden, and cognition are largely unknown. We aimed to evaluate whether CVD (lacunes, white matter hyperintensities, and microbleeds) and amyloid burden (Pittsburgh compound B [PiB] retention ratio) contribute to cognitive impairment independently or interactively. We recruited 136 patients with subcortical vascular cognitive impairment who underwent magnetic resonance imaging, PiB–positron emission tomography, and neuropsychological testing. The number of lacunes was associated with memory, frontal dysfunctions, and disease severity. The volume of white matter hyperintensities and the PiB retention ratio were associated only with memory dysfunction. There was no direct correlation between CVD markers and PiB retention ratio except that the number of lacunes was negatively correlated with the PiB retention ratio. In addition, there were no interactive effects of CVD and PiB retention ratio on cognition. Our findings suggest that CVD and amyloid burden contribute independently and not interactively to specific patterns of cognitive dysfunction in patients with subcortical vascular cognitive impairment.

We describe new [(18)F]Fluoropropylcarbomethoxyiodophenyl-nor-tropane ([(18)F]FP-CIT) automatic preparation method by (1) using 2-methyl-2-butanol as [(18)F]fluorination solvent, (2) base amount control to minimize side reaction and (3) salt elution method to elute trapped [(18)F]fluoride. We developed manual synthesis procedures for automatic synthesis application. In this manual synthesis, we trapped [(18)F]F(-) on ion exchange cartridge and eluted with 0.2 M potassium methanesulfonate solution. We have [(18)F]fluorination at 100°C with 2-methyl-2-butanol as protic solvent for [(18)F]fluorination. After high-performance liquid chromatography analysis, we have 69.3±3.2% of [(18)F]F(-) incorporation ratio on the manual synthesis and applied these conditions to automatic preparation with GE TracerLab FX module. After setting-up of automatic synthesis and quality control procedures for clinical procedures, we have routine production of [(18)F]FP-CIT with 86.9±9.5 GBq/2.5 ml of [(18)F]F(-) as initial radioactivity and have 192 productions for 1.5 year. We have 42.5±10.9% of decay corrected radiochemical yields and they were satisfied all quality control procedures and stability to 6 h. New [(18)F]FP-CIT automatic preparation method showed high and reliable radiochemical yield and we could have enough >35 patient doses of [(18)F]FP-CIT from one production.

Imaging the pharmacodynamics of anti-cancer drugs may allow early assessment of anti-cancer effects. Increases in 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake early after thymidylate synthase inhibition (TS) inhibition, the so-called flare response, is considered to be largely due to an increase in binding sites for type-1 equilibrative nucleoside transporter. We investigated the induction of thymidine kinase 1 (TK1) after 5-fluorouracil (5-FU) treatment as one of mechanisms for [(18)F]FLT flare. Exposure of nine cancer cell lines to 5-FU for 24h induced a 2.5- to 3.5-fold increase in [(18)F]FLT uptake, significantly higher than the 1.5-fold increase observed 2h after treatment. The increase of [(18)F]FLT uptake 24h after 5-FU exposure accompanied TK1 induction in most cell lines. In representative cell lines (A431 and HT29), 5-FU time-dependently increased [(18)F]FLT uptake, kinase activity and the levels of protein and mRNA for TK1, sequential cyclin E and A induction, and G(1)-S phase transition. Cycloheximide treatment and knockdown of TK1 completely inhibited 5-FU-induced [(18)F]FLT flare. On the other hand, HCT8 cells showed a biphasic [(18)F]FLT flare with lacked TK1 induction in response to the dosage of 5-FU. Cycloheximide did not inhibit 5-FU-induced [(18)F]FLT flare in this cells. In vivo dynamic [(18)F]FLT-PET and ex vivo analysis in HT29 tumor-bearing mice showed significantly increased [(18)F]FLT flux and TK1 activity of tumor tissue 24h after 5-FU administration (P

Purpose To evaluate the efficacy of β-irradiation therapy with rhenium 188 ( 188 Re) mercaptoacetyltriglycine (MAG3)–filled balloon dilation to prevent neointimal hyperplasia after stent placement in a canine iliac artery model. Materials and Methods A total of 15 stents were implanted into the iliac arteries of eight dogs (one or two stents in each dog). Rhenium 188 MAG3–filled balloon dilation was performed immediately after placement of 10 bare stents—20 Gy in group II ( n = 5) and 40 Gy in group III ( n = 5)—and conventional balloon dilation was performed immediately after placement of the remaining five bare stents (group I). A follow-up angiogram was obtained 8 weeks after the procedure, and percentage of luminal stenosis was calculated for the proximal and distal ends of each stent. Neointimal thickening (expressed as the neointimal area divided by the sum of neointimal area and media area) was assessed for microscopic examination. Results All eight dogs survived until they were euthanized 8 weeks after the procedures. The mean luminal stenosis measurements at 8-week follow-up angiography in groups I, II, and III were 26.63%, −0.44%, and 10.53%, respectively. The mean neointimal thickening measurements in groups I, II, and III were 0.77, 0.21, and 0.34, respectively. The mean percentage of luminal stenosis and neointimal thickening differed significantly among the three groups ( P Conclusions β-Irradiation with 188 Re-MAG3–filled balloon dilation has the potential to reduce neointimal hyperplasia secondary to stent placement in a canine iliac artery model. A dose of 20 Gy may be preferable versus a dose of 40 Gy to reduce neointimal hyperplasia.

In this study, we synthesized (99m)Tc(CO)(3)-2'-aminomethylpyridyl-2'-deoxyuridine ((99m)Tc(CO)(3)-AMPDU) and (99m)Tc(CO)(3)-aminoethylpyridyl-2'-deoxyuridine ((99m)Tc(CO)(3)-AEPDU) as potential agents for imaging the expression of the non-invasive herpes simplex virus type-1 thymidine kinase. AMPDU and AEPDU were synthesized from uridine in five chemical steps and then labeled with [(99m)Tc(CO)(3)(H(2)O)(3)](+) (370MBq/0.5 mL) at 100 degrees C for 10 min. Under optimal conditions (0.5 and 1.0mg for AMPDU and AEPDU and heating for 10 min), the labeling efficiency was 95.3+/-2.8% for AMPDU and 94.2+/-5.1% for AEPDU. To validate the chemical structure of (99m)Tc(CO)(3)-labeled compounds, we also synthesized ReBr(CO)(3)-AMPDU and ReBr(CO)(3)-AEPDU by reacting [Et(4)N][ReBr(3)(CO)(3)] and AMPDU or AEPDU in methanol at 25 degrees C for 6h. (99m)Tc(CO)(3)-AMPDU and (99m)Tc(CO)(3)-AEPDU had the same retention time on HPLC analysis as ReBr(CO)(3)-AMPDU and ReBr(CO)(3)-AEPDU. (99m)Tc(CO)(3)-AMPDU and (99m)Tc(CO)(3)-AEPDU had high radiochemical stabilities of 98.1+/-1.5% and 98.0+/-1.7% for 6h, respectively.

Purpose To present the preliminary results of β irradiation with use of liquid rhenium 188 ( 188 Re)-filled balloon dilation in the treatment of refractory benign airway strictures. Materials and Methods Ten sessions of β irradiation by using liquid 188 Re-filled balloon dilation were prospectively performed in nine patients with refractory bronchial strictures between 2003 and 2006. Indications for treatment were dyspnea caused by repeat stricture or no response to previous treatment (ie, balloon dilation and/or temporary stent placement or laser therapy) in seven patients and dyspnea caused by exuberant granulation tissue formation at the distal end of the placed stent in two. To assess the treatment efficacy, the authors calculated and compared the mean intervals of interventional treatments before and after dilation with 188 Re and mercaptoacetyltriglycine (MAG 3 )–filled balloons. Results Liquid 188 Re-filled balloon dilation was successfully performed in all nine patients, with no procedure-related complications. Immediately after the procedure, all patients showed resolution of their dyspnea. Five patients remained asymptomatic at 5–25-month follow-up. Four patients experienced dyspnea caused by recurrent stricture 1–10 months after dilation. The mean intervals between interventional treatments increased significantly from 3.1 months ± 2.1 before 188 Re-MAG 3 –filled balloon dilation to 10.8 months ± 8.8 after 188 Re-MAG 3 –filled balloon dilation in all nine patients (Wilcoxon signed rank test, P = .025). Conclusions β irradiation with liquid 188 Re-filled balloon dilation can be safely used for refractory benign airway strictures. A large study with longer follow-up is needed to draw a definite conclusion.

This paper describes a novel series of stilbenylbenzoxazole (SBO) and stilbenylbenzothiazole (SBT) derivatives for beta-amyloid specific binding probes. These 24 compounds were synthesized and evaluated by competitive binding assay against beta-amyloid 1-42 (Abeta42) aggregates using [(125)I]TZDM. All the derivatives displayed higher binding affinities with K(i) value in the subnanomolar range (0.10-0.74 nM) than Pittsburgh Compound-B (PIB) (0.77 nM). Among these derivatives, SBT-2, 5-fluoroethoxy-2-{4-[2-(4-methylaminophenyl)vinyl]phenyl}benzothiazole, showed lowest K(i) value (0.10 nM). In conclusion, the preliminary results suggest that these compounds are implying a possibility as a probe for detection of Abeta fibrils in Alzheimer's disease (AD) patients.

New ferulic acid and benzothiazole dimer derivatives were synthesized and evaluated by in vitro competition assay using [(125)I]TZDM for their specific binding affinities to Abeta fibrils. In particular, 4a showed the most excellent binding affinity (K(i)=0.53 nM), compared to PIB (K(i)=0.77 nM), for benzothiazole binding sites of Abeta(1-42) fibrils. This result suggests a possibility of a potential AD diagnostic probe for detection of Abeta fibrils.

The Cu(I)-catalyzed, 1,3-dipolar cycloaddition reaction was applied successfully to the synthesis of small, F-18-labeled biomolecules, and an optimal condition was developed for one-pot, two-step reaction without any interim purifications. This technique was employed in various F-18-labeled, 1,2,3-triazole syntheses with high radiochemical yield.

We have developed a fully automatic method for the synthesis of 16 α -[ 18 F]fluoroestradiol ([ 18 F]FES) using a disposable cassette system and conventional [ 18 F]FDG module. [ 18 F]FES was synthesized using a GE TracerLab MX module and a modified module control program. Following [ 18 F]fluorination, we hydrolyzed the product three times with a mixture of 2 N HCl and CH 3 CN. After HPLC purification, the decay corrected radiochemical yield of [ 18 F]FES was 45.3±2.8%, which was stable to 98.2±0.2% at 6 h after synthesis. This new automated synthesis method provides high and reproducible yields with the advantage of a disposable cassette system.

We have developed three methods for removing organic impurities as well as a solid-phase extraction (SPE) method for removing metallic and ionic impurities from recovered [18O]H2O. Preliminary experiments with [16O]H2O were used to determine the optimal purification conditions. These showed that UV irradiation rapidly (

Although [18F] fluoropropylcarbomethoxyiodophenylnortropane (FP-CIT) is a promising radiopharmaceutical for dopamine transporter imaging, it has not been used for clinical studies because of low radiochemical yield. The purpose of our study was to develop a new radiochemistry method using a protic solvent system to obtain a high radiochemical yield of [18F]FP-CIT in single-step manual and automatic preparation procedures. [18F]F(-) was trapped on a QMA Sep-Pak cartridge or PS-HCO(3) cartridge and eluted with Cs2CO(3)/K222 buffer or TBAHCO3 respectively, or 8 microl of TBAOH was added directly to [18F]F(-)/H(2)(18)O solution in a reactor without using a cartridge. After drying, 18F] fluorination was performed with 2-6 mg of mesylate precursor, 100 microl of CH(3)CN and 500 microl of t-BuOH at 50-120 degrees C for 5-30 min, followed by high-performance liquid chromatography (HPLC) purification to obtain the final product. For comparison, the same procedure was performed with a tosylate precursor. Manual synthesis gave a decay-corrected radiochemical yield of 52.2+/-4.5%, and optimal synthesis conditions were as follows: TBAOH addition, 4 mg of precursor, 100 degrees C and 20 min of [18F] fluorination (n=3). We obtained low radiochemical yields of [18F]FP-CIT with carbonate elution systems such as Cs2CO(3) or TBAHCO3. We also developed an automatic synthesis method based on manual synthesis results. In automatic production, we obtained a decay-corrected radiochemical yield of 35.8+/-5.2% after HPLC purification, and we did not have any synthesis failures (n=14). Here, we describe our new method for the synthesis of [18F]FP-CIT using a protic solvent system. This method gave a high radiochemical yield with high reproducibility and might enable [18F]FP-CIT to be used clinically and commercially.

The development of more selective delivery systems for cancer diagnosis and chemotherapy is one of the most important goals of current anticancer research. The purpose of this study is to evaluate various self-assembled nanoparticles as candidates to shuttle radionuclide and/or drugs into tumors and to investigate the mechanisms underlying the tumor targeting with self-assembled nanoparticles. By combining different hydrophobic moieties and hydrophilic polymer backbones, various self-assembled nanoparticles were prepared, and their in vivo distributions in tumor-bearing mice were studied by radionuclide imaging. One type of nanoparticles (fluorescein isothiocyanate-conjugated glycol chitosan (FGC) nanoparticles) exhibited highly selective tumoral localization. Scintigraphic images obtained 1 day after the intravenous injection of FGC nanoparticles clearly delineated the tumor against adjacent tissues. The mechanisms underlying the tumor targeting with self-assembled nanoparticles were investigated in terms of the physicochemical properties of nanoparticles and tumor microenvironments. FGC nanoparticles were preferentially localized in perivascular regions, implying their extravasation to tumors through the hyperpermeable tumor vasculature. The magnitude and pattern of tumoral distribution of self-assembled nanoparticles were influenced by several key factors —(i) in vivo colloidal stability: nanoparticles should maintain their intact nanostructures in vivo for a long period of time, (ii) particle size, (iii) intracellular uptake of nanoparticle: fast cellular uptake greatly facilitates the tumor targeting, (iv) tumor angiogenesis: pathological angiogenesis permits access of nanoparticles to tumors. We believe that this work can provide insight for the engineering of nanoparticles and be extended to cancer therapy and diagnosis, so as to deliver multiple therapeutic agents and imaging probes at high local concentrations.

Affective symmetries, such as the positivity offset and negativity bias, have been postulated to be attributable to distinct activation functions of the positive and negative affect systems. We investigated the neural substrates that are engaged when the positive and negative affect systems undergo parallel and integrative processing. Eleven subjects were scanned using H215O PET during choosing the subjective feeling produced by a stimulation pair of pictures or words. Four different conditions were designed for contrast: pure positivity, pure negativity, positivity offset, and negativity bias. The dorsolateral prefrontal activation was associated with positivity offset and negativity bias condition, whereas the ventromedial prefrontal activation, together with limbic and subcortical activations, was associated with pure positivity and pure negativity condition. The results indicated that positivity offset and negativity bias are not merely due to asymmetric activations of the positive and negative systems, but integrative processing of higher neocortical levels is involved.

Background The long-term fate of patent irradiated segments at 6 months after β-radiation therapy has not been sufficiently evaluated. Methods Two-year follow-up angiography was performed in 52 patients with patent irradiated segments at 6 months after β-radiation with a rhenium 188–mercaptoacetyltriglycine–filled balloon for diffuse in-stent restenosis. We evaluated late recurrence (LR) and its predictors after β-radiation. Results Late recurrence at 2 years after radiation was observed in 10 (19.2%) of 52 patients. The minimal lumen diameter (MLD) progressively decreased, from 2.67 ± 0.44 mm at postprocedure to 2.42 ± 0.53 mm at 6 months to 2.09 ± 0.75 mm at 2 years ( P = .001). In the 42 patients without LR, the MLD decreased from postprocedure (2.74 ± 0.43 mm) to 6 months (2.44 ± 0.54 mm; P = .006), but did not change between 6 months and 2 years (2.35 ± 0.49 mm, P = .13). In the LR group, the MLD was unchanged from postprocedure (2.33 ± 0.29 mm) to 6 months (2.30 ± 0.43 mm; P = .81), but decreased significantly between 6 months and 2 years (1.02 ± 0.75 mm, P = .001). Multivariate analysis identified postprocedural MLD as an independent predictor of LR (odds ratio 0.025, 95% CI 0.007-0.94, P = .04). Late target lesion revascularization was performed in 6 patients (11.5%) between 6 months and 2 years after radiation. Conclusion Although LR after radiation was observed in some patients, irradiated segments remained stable for up to 2 years in most patients. Smaller postprocedural MLD, followed by delayed late loss between 6 months and 2 years, was associated with LR.

Background: Intracoronary radiation therapy for in-stent restenosis has been demonstrated to reduce restenosis and major adverse cardiac events. However, long-term angiographic and clinical outcomes after beta radiation therapy have not been sufficiently evaluated. Methods: We evaluated the long-term angiographic and clinical outcomes of 50 consecutive patients who had received beta-radiation therapy with a 188 Re-MAG 3 -filled balloon after rotational atherectomy for diffuse in-stent restenosis (lesion length>10 mm) in native coronary arteries. The radiation dose was 15 Gy at a depth of 1.0 mm into the vessel wall. Results: The mean lesion length was 25.6±12.7 mm. Radiation was delivered successfully to all patients without any procedural or in-hospital complications. At the 6-month angiogram, the restenosis rates was 10% (5/50). There were no major adverse cardiac events (MACE), such as death, myocardial infarction, and target lesion revascularization (TLR) by 6-month follow-up. Long-term clinical follow-up data were obtained in all patients during 30.1±4.5 months. No myocardial infarction and one noncardiac death occurred during follow-up. Two-year follow-up angiogram was performed in 26 (58%) of 45 patients who showed a patent radiation segment at the 6-month angiogram. Significant narrowing of diameter stenosis of more than 50% occurred in 6 (23%) of 26 patients between 6 and 24 months after beta-radiation. Late TLR was performed in 6 patients. The rate of 30-month death-free survival and MACE-free survival were 98.0±2.0% and 86.9±5.0%. Conclusion: Beta-radiation using a 188 Re-MAG 3 -filled balloon after rotational atherectomy is associated with favorable long-term angiographic and clinical outcomes.

We prepared 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) from 3'-O-nosyl thymidine derivative 3 or its pyrimidine ring N-BOC-protected analogue 5 and optimized [(18)F]fluorination condition for a high radiochemical yield. The optimal condition for [(18)F]fluorination with precursor 3 was 30 mg (41.1 micromol)/300 microl CH(3)CN at 130 degrees C for 5 min, while precursor 5 required 34 mg (40 micromol)/300 microl CH(3)CN at 110 degrees C for 5 min. After HPLC purification at neutral pH, we achieved high radiochemical yields of 40 +/- 5.2% and 42 +/- 5.4% (decay-corrected) within 60 min of preparation time with radiochemical purities of97%.

We describe here the synthesis of 99mTc-ciprofloxacin by four different methods and its biodistribution. All of the methods gave high radiochemical yields of > or = 90% and high stability of > or = 90% at 6 h after preparation. However HPLC analysis, bacterial binding assay, and in vivo distribution for the four 99mTc-ciprofloxacins showed different results. Among these methods, the use of formamidine sulfinic acid with microwave heating (Method A) was fast and easy, and gave more desirable biological properties than the other methods.

Background The impacts of geographic miss on edge restenosis have not been sufficiently evaluated. Methods β-Radiation therapy with rhenium 188–filled balloon after rotational atherectomy for diffuse in-stent restenosis was performed in 50 patients. We evaluated the impacts of geographic miss on adjacent coronary artery segments beyond the stent by angiographic (QCA) and intravascular ultrasound (IVUS) analysis in 50 irradiated lesions and 100 edges. Serial IVUS and QCA comparisons between postradiation and 6 months' follow-up were available in 44 and 47 of 50 patients, respectively. QCA measurements of minimal lumen diameter (MLD) and IVUS analysis were performed in the reference and radiation segments. Edges that were touched by the angioplasty balloon but were not adequately covered by radiation constituted the geographic miss edges. Results Geographic miss was observed in 55.6% and 52.6% in QCA and IVUS analysis, respectively. Edge restenosis after radiation therapy in 3 patients was associated with geographic miss. In contrast to uninjured edges (postradiation 2.9 ± 0.6 mm to follow-up 2.8 ± 0.6 mm, P =.292), MLD in the radiation segment by QCA analysis significantly decreased from 2.7 ± 0.4 mm to 2.4 ± 0.6 mm in geographic miss edges ( P =.002). IVUS analysis showed that significant positive remodeling in the radiation segment occurred in uninjured edges (vessel area from 15.4 ± 4.4 mm 2 to 15.8 ± 4.4 mm 2 , P =.001) but not in geographic miss edges (vessel area from 12.8 ± 3.6 mm 2 to 13.0 ± 3.6 mm 2 , P =.119). Conclusion The geographic miss might be one of the predictors, which resulted in decreased MLD at follow-up in β-radiation therapy. Sufficient lesion coverage with radiation might be associated with positive remodeling in the radiation segment. (Am Heart J 2002;143:327-33.)

We synthesized novel (18)F-labeled acetylcholinesterase (AChE) inhibitors, 3-[1-(3- and 4-[(18)F]fluoromethylbenzyl)piperidin-4-yl]-1-(1-methyl-1H-i ndol-3-yl )propan-1-ones ([(18)F]1 and [(18)F]2) and 3-[1-(4-[(18)F]fluorobenzyl)piperidin-4-yl]-1-(1-methyl-1H-i ndol-3-yl )propan-1-one ([(18)F]3) in high yields (decay-corrected, 25%-40%) and with high effective specific activities (>37 GBq/micromol). Tissue distribution studies of the [(18)F]1 and the [(18)F]3 in mice showed the nonspecific bindings in brain regions, with metabolic defluorination of the [(18)F]1. The result suggests that these radioligands may not be suitable agents for in vivo mapping of AChE, despite their potent in vitro anti-AChE activities.

We re-evaluated 3-bromo-1-trifluoromethanesulfonyloxypropane (3-bromopropyl triflate, 1) as the precursor for the preparation of the fluorine-18 labeled compound 2 by reoptimizing fluorine-18 incorporation reaction conditions (120°C) and developing a method to inactivate the unreacted triflate precursor (water treatment). This new reaction condition enabled us to prepare 3-[18F]fluoropropyl bromide (2) in high yield. It was used for the synthesis of a N-fluoropropyl derivative such as N-(3-[18F]fluoropropyl)spiperone ([18F]FPSP, 3) with high chemical purity.

We have prepared 4-[18F]fluoromethylbenzylsulfonate esters as fluoromethylbenzylating agents. These agents are readily prepared by an [18F]fluoride ion displacement of the corresponding bissulfonate esters. The application of these 4-[18F]fluoromethylbenzylsulfonate esters to N-alkylation reaction of spiperone and 1-phenylpiperazine shows that the products 3-N-(4-[18F]fluoromethylbenzyl)spiperone and 1-N-(4-[18F]fluoromethylbenzyl)-4-phenylpiperazine are rapidly produced with high radiochemical yields under a no-carrier-added condition.