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The aim of this work was to evaluate Gd-FC705, a prostate-specific membrane antigen (PSMA)-targeted MRI contrast agent. The r

We developed a novel therapeutic radioligand, [177Lu]1h, with an albumin binding motif and evaluated it in a prostate-specific membrane antigen (PSMA)-expressing tumor xenograft mouse model. Fourteen PSMA target candidates were synthesized, and binding affinity was evaluated with an in vitro competitive binding assay. First, four compound candidates were selected depending on binding affinity results. Next, we selected four compounds ([68Ga]1e, [68Ga]1g, [68Ga]1h, and [68Ga]1k) were screened for tumor targeting efficiency by micro–positron emission tomography/computed tomography (micro-PET/CT) imaging. Finally, [177Lu]1h compound was evaluated the tumor targeting efficiency and therapeutic efficiency by micro–single-photon emission computed tomography/computed tomography (micro-SPECT/CT), biodistribution, and radiotherapy studies. Estimated human effective dose was calculated by biodistribution data. Compound 1h showed a high binding affinity (Ki value = 4.08 ± 0.08 nmol/L), and [177Lu]1h showed extended blood circulation (1 hour = 10.32 ± 0.31, 6 hours = 2.68 ± 1.07%ID/g) compared to [177Lu]PSMA-617 (1 h = 0.17 ± 0.10%ID/g). [177Lu]1h was excreted via the renal pathway and showed high tumor uptake (24.43 ± 3.36%ID/g) after 1 hour, which increased over 72 hours (72 hours = 51.39 ± 9.26%ID/g). Mice treated with 4 and 6 MBq of [177Lu]1h showed a median survival rate of >61 days. In particular, all mice treated with 6 MBq of [177Lu]1h survived for the entire monitoring period. The estimated human effective dose of [177Lu]1h was 0.07 ± 0.01 and 0.03 ± 0.00 mSv/MBq in total body and kidney, respectively. The current study indicates that [177Lu]1h has the potential for further investigation of metastatic castration-resistant prostate cancer (mCRPC) therapy in clinical trials.

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

We developed a novel therapeutic radioligand, [177Lu]1h, with an albumin binding motif and evaluated it in a prostate-specific membrane antigen (PSMA)-expressing tumor xenograft mouse model. Fourteen PSMA target candidates were synthesized, and binding affinity was evaluated with an in vitro competitive binding assay. First, four compound candidates were selected depending on binding affinity results. Next, we selected four compounds ([68Ga]1e, [68Ga]1g, [68Ga]1h, and [68Ga]1k) were screened for tumor targeting efficiency by micro–positron emission tomography/computed tomography (micro-PET/CT) imaging. Finally, [177Lu]1h compound was evaluated the tumor targeting efficiency and therapeutic efficiency by micro–single-photon emission computed tomography/computed tomography (micro-SPECT/CT), biodistribution, and radiotherapy studies. Estimated human effective dose was calculated by biodistribution data. Compound 1h showed a high binding affinity (Ki value = 4.08 ± 0.08 nmol/L), and [177Lu]1h showed extended blood circulation (1 hour = 10.32 ± 0.31, 6 hours = 2.68 ± 1.07%ID/g) compared to [177Lu]PSMA-617 (1 h = 0.17 ± 0.10%ID/g). [177Lu]1h was excreted via the renal pathway and showed high tumor uptake (24.43 ± 3.36%ID/g) after 1 hour, which increased over 72 hours (72 hours = 51.39 ± 9.26%ID/g). Mice treated with 4 and 6 MBq of [177Lu]1h showed a median survival rate of >61 days. In particular, all mice treated with 6 MBq of [177Lu]1h survived for the entire monitoring period. The estimated human effective dose of [177Lu]1h was 0.07 ± 0.01 and 0.03 ± 0.00 mSv/MBq in total body and kidney, respectively. The current study indicates that [177Lu]1h has the potential for further investigation of metastatic castration-resistant prostate cancer (mCRPC) therapy in clinical trials.

[177Lu]Ludotadipep, which enables targeted delivery of beta-particle radiation to prostate tumor cells, had been suggested as a promising therapeutic option for mCRPC. From November 2020 to March 2022, a total of 30 patients were enrolled for single dose of [177Lu]Ludotadipep RPT, 6 subjects in each of the 5 different activity groups of 1.9 GBq, 2.8 GBq, 3.7 GBq, 4.6 GBq, and 5.6 GBq. [177Lu]Ludotadipep was administered via venous injection, and patients were hospitalized for three days to monitor for any adverse effects. Serum PSA levels were followed up at weeks 1, 2, 3, 4, 6, 8, and 12, and PSMA PET/CT with [18F]Florastamin was obtained at baseline and again at weeks 4 and 8. The subjects required positive PSMA PET/CT prior to [177Lu]Ludotadipep administration. Among the 29 subjects who received [177Lu]Ludotadipep, 36 treatment emergent adverse events (TEAEs) occurred in 17 subjects (58.6%) and 4 adverse drug reactions (ADRs) in 3 subjects (10.3%). Of the total 24 subjects who had full 12-week follow-up data, 16 (66.7%) showed decrease in PSA of any magnitude, and 9 (37.5%) showed a decrease in PSA by 50% or greater. A total of 5 of the 24 patients (20.8%) showed disease progression (PSA increase of 25% or higher from the baseline) at the 12th week following single dose of [177Lu]Ludotadipep. These data thus far suggest that [177Lu]Ludotadipep could be a promising RPT agent with low toxicity in mCRPC patients who have not been responsive to conventional treatments.

The trifluoromethyl group is a prominent motif in biologically active compounds and therefore of great interest for the labeling with the positron emitter fluorine-18 for positron emission tomography (PET) imaging. Multiple labeling strategies have been explored in the past; however, most of them suffer from low molar activity due to precursor degradation. In this study, the potential of 1-(difluoromethyl)-3-methyl-4-phenyl-1H-1,2,3-triazol-3-ium triflate as precursor for the synthesis of the [18 F]trifluoromethylation building block [18 F]fluoroform with high molar activity was investigated. The triazolium precursor was reacted under various conditions with [18 F]fluoride, providing [18 F]fluoroform with radiochemical yields (RCY) and molar activities (Am ) comparable and even superior with already existing methods. Highest molar activities (Am = 153 ± 14 GBq/μmol, dc, EOS) were observed for the automated procedure on the Neptis® perform module. Due to its easy handling and good RCY and Am in the [18 F]fluoroform synthesis, the triazolium precursor is a valuable alternative to already known precursors.

α-Ketoamides are an important key functional group and have been used as versatile and valuable intermediates and synthons in a variety of functional group transformations. Synthetic methods for making aryl α-ketoamides as drug candidates have been greatly improved through metal-catalyzed aerobic oxidative amidations. However, the preparation of alkyl α-ketoamides through metal-catalyzed aerobic oxidative amidations has not been reported because generating α-ketoamides from aliphatic ketones with two α-carbons theoretically provides two distinct α-ketoamides. Our strategy is to activate the α-carbon by introducing an N-substituent at one of the two α-positions. The key to this strategy is how heterocyclic compounds such as triazoles and imidazoles affect the selectivity of the synthesis of the alkyl α-ketoamides. From this basic concept, and by optimizing the reaction and elucidating the mechanism of the synthesis of aryl α-ketoamides via a copper-catalyzed aerobic oxidative amidation, we prepared fourteen aliphatic α-ketoamides in high yields (48–84%).

The synthesis of fluorine-18 labeled fluoroform with high molar activity has grown in importance for the development of fluorine-18 labeled aryl-CF3 radiopharmaceuticals that are useful as diagnostic radiotracers for the powerful technique of positron emission tomography (PET). We designed a strategy of synthesizing fluorine-18 labeled fluoroform from N1-difluoromethyl-N3-methyltriazolium triflate (1) via SN2 fluorination without stable fluorine isotope scrambling. Fluoroform was generated at rt in 10 min by fluorination of the triazolium precursor with TBAF (6 equiv.). We propose three routes (a), (b), and (c) for this fluorination. Quantum chemical calculations have been carried out to elucidate the mechanism of experimentally observed nucleophilic attack of fluoride at difluoromethyl group via route (a), not N3-methyl via route (b). 1H and 19F NMR studies using deuterium source have been performed to examine the competition between SN2 fluorination (route (a)) and the formation of difluorocarbene (route (c)). The observed superiority of SN2 pathway to formation of difluorocarbene in the reaction of the precursor using CsF in (CD3CN/(CD3)3COD (17.8 : 1)) gives the possibility of preparing the fluorine-18 labeled fluoroform in high molar activity.

We have compared the similarity of the in vivo distribution of the prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging agents [18F]DCFPyL, [68Ga]ludotadipep, and [68Ga]PSMA-11. This study is designed for a further selection of a PSMA-targeted PET imaging agent for the therapeutic evaluation of [177Lu]ludotadipep, our previously developed prostate-specific membrane antigen (PSMA)-targeted prostate cancer therapeutic radiopharmaceutical. In vitro cell uptake was performed to evaluate the affinity to PSMA using PSMA + PC3-PIP, and PSMA − PC3-flu was used for the study. MicroPET/CT 60 min dynamic imaging and biodistribution were performed at 1, 2, and 4 h after injection. Autoradiography and immunohistochemistry were performed to evaluate the PSMA + tumor target efficiency. In the microPET/CT image, [68Ga]PSMA-11 showed the highest uptake in the kidney among all three compounds. [18F]DCFPyL and [68Ga]PSMA-11 showed similar patterns of in vivo biodistribution and high tumor targeting efficiency, similar to those of [68Ga]ludotadipep. All three agents showed high uptake in tumor tissue on autoradiography, and PSMA expression was confirmed by immunohistochemistry. Thus, [18F]DCFPyL or [68Ga]PSMA-11 can be used as a PET imaging agent to monitor [177Lu]ludotadipep therapy in prostate cancer patients.

Background Prostate-specific membrane antigen (PSMA) is increasingly recognized as an excellent target for prostate cancer imaging and therapy. Finding compounds with a high target-to-nontarget ratio are an important challenge in the development of positron emission tomography (PET) imaging agents. In this study, we attempted to find a suitable compound from a simply-synthesized compound library. Method 18 F-labeling was achieved in a two-step synthesis consisting of [18 F]fluorination of azido sulfonates followed by copper(I)-catalyzed click ligation. In vitro binding experiment and in vivo studies were carried out using isogenic PSMA+ PC3-PIP and PSMA- PC3-flu cells and 22RV1 cells. [125 I]MIP-1095 was used to measure the binding affinities of compounds through a competitive binding assay, and [18 F]DCFPyL was used for a comparative assessment of compounds. Radiation dosimetry data were obtained using OLINDA/EXM software. Results Nine novel PSMA ligands were synthesized by the combination of three azido compounds and three terminal acetylene-containing Glu-urea-Lys compounds. Among them, compound 6f having a pyridine moiety showed a high binding affinity of 6.51 ± 0.19 nM (Ki ). 18 F-labeled compounds were obtained at moderate yields within 70 to 75 minutes (including high-performance liquid chromatography purification). Compound [18 F]6c had the lowest log P of -2.693. MicroPET/computed tomography (CT) images were acquired from 22RV1 cell xenograft mice after injecting [18 F]6c, [18 F]6f, and [18 F]6i. Additional microPET/CT experiments of [18 F]6c and [18 F]6f were performed using PSMA+ PC3-PIP and PSMA- PC3-flu cell-bearing mice. [18 F]6c was selected for further studies because it was found to have high uptake in tumors and rapid renal clearance, resulting in great tumor-to-nontumor ratios and distinct tumor images with very low background activity. Human dosimetry estimation of [18 F]6c using OLINDA/EXM software was calculated, resulting in an effective dose of 4.35 × 10-3 mSv/MBq. Conclusions [18 F]6c showed significant tumor uptake, a high tumor-to-nontumor ratio, and good radiation dosimetry results, suggesting further development as a potential diagnostic PET agent for prostate cancer.

To evaluate the biodistribution of [18F]Florastamin, a novel 18F-labelled positron emission tomography (PET) tracer for prostate-specific membrane antigen (PSMA) for the diagnosis of prostate cancer. PET was performed for five healthy controls and 10 patients with prostate cancer at 0, 10, 30, 70, and 120 mins after injecting 370 MBq of [18F]Florastamin. The maximum standardised uptake value (SUVmax) was evaluated in the primary tumour. The mean SUVmax (SUVmean) was evaluated in normal organs. Furthermore, the residence time was evaluated by assessing radioactivity in each organ. The internal radiation dosimetry was calculated using the OLINDA/EXM software. The SUVmax in primary tumours increased with time. A favourable tumour to background ratio was also observed over time. Multiple lymph nodes and bone metastases were also evaluated and showed a similar pattern to SUVmax in the primary tumour. In one patient, a tiny lymph node metastasis was identified using [18F]Florastamin PET, which was not observed using other modalities, and was histologically confirmed. The highest absorbed dose was observed in the kidney (0.062 ± 0.015 mGy/MBq), followed by the bladder (0.032 ± 0.013 mGy/MBq), liver (0.022 ± 0.006 mGy/MBq), and salivary gland (0.018 ± 0.006 mGy/MBq). The effective dose with a 370 MBq injection of [18F]Florastamin was 1.81 mSv. No adverse events related to [18F]Florastamin were reported. We identified a novel PSMA-targeted PET ligand, [18F]Florastamin, for imaging prostate cancer. [18F]Florastamin showed a high SUVmax and relatively high tumour to background ratio in both primary tumour and metastatic lesions, which suggests its high sensitivity to detect tumours without any adverse events. KCT0003924 registered at https://cris.nih.go.kr/ .

The trifluoromethyl group is a prominent motif in biologically active compounds and therefore of great interest for the labeling with the positron emitter fluorine-18 for positron emission tomography (PET) imaging. Multiple labeling strategies have been explored in the past; however, most of them suffer from low molar activity due to precursor degradation. In this study, the potential of 1-(difluoromethyl)-3-methyl-4-phenyl-1H-1,2,3-triazol-3-ium triflate as precursor for the synthesis of the [

Purpose The aim of the present study was to obtain information about distribution, radiation dosimetry, toxicity, and pharmacokinetics of O-[18F]fluoromethyl-D-tyrosine (D-18F-FMT), an amino acid PET tracer, in patients with brain tumors. Patients and methods A total of 6 healthy controls (age = 19-25 years, 3 males and 3 females) with brain PET images and radiation dosimetry and 12 patients (median age = 60 years, 6 males and 6 females) with primary (n = 5) or metastatic brain tumor (n = 7) were enrolled. We acquired 60-minute dynamic brain PET images after injecting 370 MBq of D-18F-FMT. Time-activity curves of D-18F-FMT uptake in normal brain versus brain tumors and tumor-to-background ratio were analyzed for each PET data set. Results Normal cerebral uptake of D-18F-FMT decreased from 0 to 5 minutes after injection, but gradually increased from 10 to 60 minutes. Tumoral uptake of D-18F-FMT reached a peak before 30 minutes. Tumor-to-background ratio peaked at less than 15 minutes for 8 patients and more than 15 minutes for 4 patients. The mean effective dose was calculated to be 13.2 μSv/MBq. Conclusions Using D-18F-FMT as a PET radiotracer is safe. It can distinguish brain tumor from surrounding normal brain tissues with a high contrast. Early-time PET images of brain tumors should be acquired because the tumor-to-background ratio tended to reach a peak within 15 minutes after injection.

α-Ketoamides are an important key functional group and have been used as versatile and valuable intermediates and synthons in a variety of functional group transformations. Synthetic methods for making aryl α-ketoamides as drug candidates have been greatly improved through metal-catalyzed aerobic oxidative amidations. However, the preparation of alkyl α-ketoamides through metal-catalyzed aerobic oxidative amidations has not been reported because generating α-ketoamides from aliphatic ketones with two α-carbons theoretically provides two distinct α-ketoamides. Our strategy is to activate the α-carbon by introducing an N-substituent at one of the two α-positions. The key to this strategy is how heterocyclic compounds such as triazoles and imidazoles affect the selectivity of the synthesis of the alkyl α-ketoamides. From this basic concept, and by optimizing the reaction and elucidating the mechanism of the synthesis of aryl α-ketoamides via a copper-catalyzed aerobic oxidative amidation, we prepared fourteen aliphatic α-ketoamides in high yields (48-84%).

The synthesis of fluorine-18 labeled fluoroform with high molar activity has grown in importance for the development of fluorine-18 labeled aryl-CF

For the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), variable neuroimaging and neuropsychological tests have been used. We aimed to evaluate the correlation of neuropsychological domain with new amyloid positron emission tomography (PET) study and to validate the availability of new PET tracer. We enrolled 20 patients who underwent 11C-PiB-PET/CT, new PET tracer 18F-FC119S PET/CT from November, 2014 to July, 2015. Among them, 10 patients were diagnosed with AD and 10 patients with MCI. The current version of Seoul Neuropsychological Screening Battery (SNSB) II was performed for cognitive evaluation. Each parameter of SNSB was compared between 2 patient groups. Spearman correlation analysis between value of SNSB domain and standardized uptake value ratio (SUVR) of PET was also performed. The AD group presented significant poor z-score in Korean-Boston Naming Test(K-BNT) (P = .01),copy score of Rey Complex Figure Test (RCFT) (P = .049), immediate (P = .028)and delayed memory of Seoul Verbal Learning Test (SVLT) (P = .028), recognition of RCFT (P = .004), “animal” of Controlled Oral Word Association Test (COWAT) (P = .041), color reading of Korean-Color Word Stroop test (K-CWST) (P = .014), and Digit Symbol Coding (DSC) (P = .007) compared with MCI group. That means, except attention domain, all other cognitive domains were relatively impaired in AD compared with MCI. In correlation analysis, we found that poor performances on copy score of RCFT in MCI groups were associated with great beta amyloid burden in frontal area in both 11C-PiB-PET/CT and 18F-FC119S PET/CT. In AD group, 18F-FC119S PET presented more extensive correlation in each cognitive domain with multiple cortical areas compared with 11C-PiB-PET. The degree of amyloid burden assessed on 18F-FC119S PET was significantly correlated with neuropsychological test in AD, and also MCI patients. The combination of neuropsychological evaluation with novel 18F-FC119S PET/CT can be used for valid biomarker for MCI and AD.

A radiolabeled amino acid O-[18F]fluoromethyl-D-tyrosine (D-[18F]FMT) has been reported to show high tumor uptake. However, introduction of [18F]fluoromethyl group was difficult and was an issue to be solved. We solved it by using a precursor containing 1,2,3-triazolium salt. D-[18F]FMT was synthesized from (R)-1-((4-(2-((tert-butoxycarbonyl)amino)-3-((3,4-dimethylbenzyl)oxy)-3-oxopropyl)phenoxy)methyl)-3-methyl-4-phenyl-1H-1,2,3-triazol-3-ium trifluoromethanesulfonate via intra-molecular 18F-fluorination and subsequent removal of the protecting groups. The total synthesis time was 65min (including purification) and the overall radiochemical yield was 9% based on the isolated product (not decay-corrected). The resulting D-[18F]FMT was obtained with high radiochemical purity (> 99%) and specific activity (100-150 GBq/μmol). D-[18F]FMT also achieved excellent results in pharmacological evaluation such as stability test and protein binding assay. We expect that this simple one-pot labeling method would help using D-[18F]FMT more widely.

The highly regioselective and efficient synthesis of diverse substituted-benzothiazoles, including heterocyclic units and amino groups, was achieved in moderate to high yields from ortho-bromothiobenzanilides, ortho-bromoarylthioureas, ortho-bromobenzanilides, and ortho-dibromobenzanilides, regardless of the electron density and substituted positions, via the prevalent carbon-sulfur bond formation by thermally induced intramolecular cyclization reaction without using any metal sources or other additives. Polysubstituted-benzothiazoles, particularly 2,4-, 2,6-disubstituted, and 2,4,6-trisubstituted benzothiazoles, could be efficiently synthesized by a facile cascade reaction from appropriate ortho-bromobenzanilides under general thiolation conditions. This benign reaction represents a straightforward and practical approach toward diverse substituted-benzothiazoles. In addition, the remaining bromine substituent of the resulting products was further utilized as a functional handle for the additional diversification and exploited as a complementary solution for the adjustment of harsh reaction condition. This methodology not only allows for the elaboration of benzothiazole molecules, but also provides a new valuable synthetic tool for a range of pharmaceutical applications.

To evaluate the efficacy of 18F-FC119S as a positron emission tomography (PET) radiopharmaceutical for the imaging of Alzheimer’s disease (AD), we studied the drug absorption characteristics and distribution of 18F-FC119S in normal mice. In addition, we evaluated the specificity of 18F-FC119S for β-amyloid (Aβ) in the AD group of an APP/PS1 mouse model and compared it with that in the wild-type (WT) group. The behavior of 18F-FC119S in the normal mice was characteristic of rapid brain uptake and washout patterns. In most organs, including the brain, 18F-FC119S reached its maximum concentration within 1 min and was excreted via the intestine. Brain PET imaging of 18F-FC119S showed highly specific binding of the molecule to Aβ in the cortex and hippocampus. The brain uptake and binding values for the AD group were higher than those for the WT group. These results indicated that 18F-FC119S would be a candidate PET imaging agent for targeting Aβ plaque.

A copper-catalyzed aerobic oxidative C N bond cleavage reaction was developed for the synthesis of 4-substituted-NH-1,2,3-triazoles. Diverse β-ketotriazoles derivatives, which are the starting materials for the aerobic oxidative C N bond cleavage reaction, were prepared from nine aryl and seven alkyl alkynes and α-azidoacetophenone by a copper(I)-catalyzed [3 + 2]cycloaddition reaction. The aerobic oxidation of α-(1,2,3-triazol-1-yl)acetophenones using a catalytic amount of copper(II) acetate in the presence oxygen under neutral conditions gave the title compounds in high yield.

Background and purpose The aim of this study was to determine the diagnostic performance and safety of a new ¹⁸F-labeled amyloid tracer, ¹⁸F-FC119S. Methods This study prospectively recruited 105 participants, comprising 53 with Alzheimer's disease (AD) patients, 16 patients with dementia other than AD (non-AD), and 36 healthy controls (HCs). In the first screening visit, the Seoul Neuropsychological Screening Battery cognitive function test was given to the dementia group, while HC subjects completed the Korean version of the Mini Mental State Examination. Individuals underwent ¹⁸F-FC119S PET, ¹⁸F-fluorodeoxyglucose (FDG) PET, and brain MRI. The diagnostic performance of ¹⁸F-FC119S PET for AD was compared to a historical control (comprising previously reported and currently used amyloid-beta PET agents), ¹⁸F-FDG PET, and MRI. The standardized uptake value (SUV) ratio (ratio of the cerebral cortical SUV to the cerebellar SUV) was measured for each PET data set to provide semiquantitative analysis. All adverse effects during the clinical trial periods were monitored. Results Visual assessments of the ¹⁸F-FC119S PET data revealed a sensitivity of 92% and a specificity of 84% in detecting AD. ¹⁸F-FC119S PET demonstrated equivalent or better diagnostic performance for AD detection than the historical control, ¹⁸F-FDG PET (sensitivity of 80.0% and specificity of 76.0%), and MRI (sensitivity of 98.0% and specificity of 50.0%). The SUV ratios differed significantly between AD patients and the other groups, at 1.44±0.17 (mean±SD) for AD, 1.24±0.09 for non-AD, and 1.21±0.08 for HC. No clinically significant adverse effects occurred during the trial periods. Conclusions ¹⁸F-FC119S PET provides high sensitivity and specificity in detecting AD and therefore may be considered a useful diagnostic tool for AD.

Divergent functionalized 8-methoxyquinaldines were synthesized via regioselective debromination, 1,3-bromine shift process, aromatization with treatment of a strong base, nucleophilic substitution reaction at the C7 position using amines and cyanide as a nucleophile in the absence of a metal source and a catalyst from an unusual electrophilic aromatic addition (AdEAr) reaction products 7 and 8. In addition, quinaldine-7,8-dione was prepared by presence of CAN (ceric ammonium nitrate) in AcOH and H2O for 10 min at room temperature from N-(alkylamino)-8-methoxyquinalidines. During the AdEAr reaction, new stereoselective dearomatized addition products were generated via discriminative reaction routes depending on the methoxy and bromine occupancy position. The AdEAr reaction not only allowed for the functionalization of electron rich-fused heterocyclic arenes, but also provided a new synthetic route to an alternative mechanism for electrophilic aromatic substitution reactions.

There has been great interest in the chemistry, syntheses and reactivities of heteroaryl-N-difluoromethane. The present work is based on the addition reaction of difluoromethyl anions, which are generated directly from difluoromethyl heterocycles, to benzophenone and benzaldehyde. As 1,2,3-triazoles and benzotriazoles can act as leaving groups, two reaction pathways are expected to exist: either the desired reaction route - deprotonation (formation of difluoromethyl anion) or the unfavored reaction route – the formation of difluorocarbene. We describe the chemistry for the selective addition reactions of difluoromethyltriazoles to ketones and aldehydes without the formation of difluorocarbene. Addition reactions of 1-(difluoromethyl)-1H-benzotriazole 1 to benzophenone 2 using potassium t-butoxide as a base were found to proceed smoothly at 0 °C for 5 min with high yields (80–88%). A plausible mechanism for the addition reactions of 1-(difluoromethyl)-1H-benzotriazole 1 and 1-difluoromethyl-4-phenyltriazole 5 to benzophenones and benzaldehydes is proposed based on deuterium-quenching experiments.

Purpose. 18F-FC119S is a positron emission tomography (PET) tracer for imaging β-amyloid (Aβ) plaques in Alzheimer’s disease (AD). The aim of this study is to evaluate the efficacy of 18F-FC119S in quantitating Aβ 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 Aβ was quantified as the distribution volume ratio using Logan graphical analysis with the cerebellum as a reference tissue. The Aβ 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 Aβ deposition in the cortex and hippocampus in contrast to the WT group. Conclusion. These results demonstrated that 18F-FC119S PET can successfully distinguish Aβ depositions in 5xFAD mice from WT.

Purpose. 18F-FC119S is a positron emission tomography (PET) tracer for imaging β-amyloid (Aβ) plaques in Alzheimer's disease (AD). The aim of this study is to evaluate the efficacy of 18F-FC119S in quantitating Aβ 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 Aβ was quantified as the distribution volume ratio using Logan graphical analysis with the cerebellum as a reference tissue. The Aβ 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 Aβ deposition in the cortex and hippocampus in contrast to the WT group. Conclusion. These results demonstrated that 18F-FC119S PET can successfully distinguish Aβ depositions in 5xFAD mice from WT.

A radiolabeled amino acid O-[

To develop radiotracer for the translocator protein 18 kDa (TSPO) in vivo, N-(2-[(18)F]fluoromethoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([(18)F]1, [(18)F]fluoromethyl-PBR28) was prepared by incorporating of fluorine-18 into triazolium triflate-PBR28 precursor (7). The radiochemical yield of [(18)F]1 after HPLC purification was 35.8 ± 3.2% (n = 11, decay corrected). Radiotracer [(18)F]1 was found to be chemically stable when incubated in human serum for 4 h at 37 °C. Both aryloxyanilide analogs (1 and 2) behaved similarly in terms of lipophilicity and in vitro affinity for TSPO. Here, both radiotracers were directly compared in the same inflammatory rat to determine whether either radiotracer provides more promising in vivo TSPO binding. Uptake of [(18)F]1 in the inflammatory lesion was comparable to that of [(11)C]PBR28, and [(18)F]1 rapidly approached the highest target-to-background ratio at early imaging time (35 min postinjection versus 85 min postinjection for [(11)C]PBR28). These results suggest that [(18)F]1 is a promising radiotracer for imaging acute neuroinflammation in rat. In addition, our use of a triazolium triflate precursor for [(18)F]fluoromethyl ether group provides the convenient application for radiofluorination of radiotracer containing a methoxy group.

Neuroinflammation is believed to be involved in the pathogenesis of neurodegenerative diseases. Our novel synthetic compound 2-acetyl-1-ethyl-7-hydroxy-6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline (AETIQ) was tested for its anti-inflammatory properties in activated microglial BV-2 cells. AETIQ attenuated nitric oxide (NO) and reactive oxygen species generation. It also downregulated the production of the proinflammatory enzymes inducible NO synthase, cyclooxygenase-2, and matrix metalloproteinase-3 at both mRNA and protein levels. Furthermore, AETIQ suppressed generation of the proinflammatory cytokines IL-1β and TNF-α as determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and ELISA assays. AETIQ attenuated NFκB signaling by downregulating NFκB nuclear translocation. The compound was stable against the liver enzymes in the microsomal and S9 fractions, indicative of good bioavailability. These results suggested that AETIQ might be utilized towards development of a therapy for neuroinflammation-related diseases.