The sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions are both bioorthogonal and mutually orthogonal, used for simultaneous labeling of two targets.

Translation of new 18F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for 18F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful 18F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [18F]fluoride of human doses of [18F]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [18F]5-fluorouracil precursor. Routine production of >10 mCi doses of [18F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [18F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated 18F-fluorination.

Apractical method for radiofluorination of anilines with [ 18 F]fluoride via N-arylsydnone intermediates is described. These precursors are stable,e asy to handle and facilitate direct and regioselective 18 F-labeling to prepare [ 18 F]fluoroarenes.T he value of this methodology is further highlighted by successful application to prepare an 18 F-labeled neuropeptide.

A practical method for radiofluorination of anilines with [18F]fluoride via N-arylsydnone intermediates is described. These precursors are stable, easy to handle and facilitate direct and regioselective 18F-labeling to prepare [18F]fluoroarenes. The value of this methodology is further highlighted by successful application to prepare an 18F-labeled neuropeptide.

A diverse series of 22 indolyl-1,2,4-triazole congeners (6 and 7) have been synthesized from the reaction of indole-3-carbonitrile (4) or (5) with appropriate acid hydrazides in the presence of potassium carbonate. Synthesized compounds were evaluated for their cytotoxicity against six human cancer cell lines, and some of the compounds displayed promising activity. In particular, 3-(3',4',5'-trimethoxyphenyl)-5-(N-methyl-3'-indolyl)-1,2,4-triazole (7i) and 3-(4'-piperidinyl)-5-(N-methyl-3'-indolyl)-1,2,4-triazole (7n) were the most promising and broadly active compounds against the tested cell lines. It was interesting to note that the trimethoxyphenyl analog 7i showed twofold selective cytotoxicity against PaCa2 cell line (IC(50) 0.8 μm), whereas piperidinyl analog 7n was found to be selectively cytotoxic against MCF7 cell line (IC(50) 1.6 μm). Notably, the 4-fluorophenyl derivative 7c exhibited selective cytotoxicity against PC3 cell line (IC(50) 4 μm). The structure-activity relationship study revealed that substituents including 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 4-piperidinyl, 4-fluorophenyl and N-methylindole are beneficial for the activity of indolyl-1,2,4-triazoles (6 and 7).

Concentration of [F]fluoride has been mentioned in literature, however, reports have lacked details about system designs, operation, and performance. Here, we describe in detail a compact, fast, fully-automated concentration system based on a micro-sized strong anion exchange cartridge. The concentration of radionuclides enables scaled-up microfluidic synthesis. Our system can also be used to provide highly concentrated [F]fluoride with minimal water content. We demonstrate how the concentrator can produce varying concentrations of [F]fluoride for the macroscale synthesis of N-boc-5-[F]fluoroindole without an azeotropic drying process, while enabling high starting radioactivity. By appropriate choice of solid-phase resin, flow conditions, and eluent solution, we believe this approach can be extended beyond [F]fluoride to other radionuclides.

Edited by George N. DeMartino Notch signaling is reported to be deregulated in several malignancies, including breast, and the enzyme ␥-secretase plays an important role in the activation and nuclear translocation of Notch intracellular domain (NICD). Hence, pharmacological inhibition of ␥-secretase might lead to the subsequent inhibition of Notch signaling in cancer cells. In search of novel ␥-secretase inhibitors (GSIs), we screened a series of triazolebased compounds for their potential to bind ␥-secretase and observed that 3-(34,5-trimethoxyphenyl)-5-(N-methyl-3-indolyl)-1,2,4-triazole compound (also known as NMK-T-057) can bind to ␥-secretase complex. Very interestingly, NMK-T-057 was found to inhibit proliferation, colony-forming ability, and motility in various breast cancer (BC) cells such as MDA-MB-231, MDA-MB-468, 4T1 (triple-negative cells), and MCF-7 (estrogen receptor (ER)/progesterone receptor (PR)-positive cell line) with negligible cytotoxicity against noncancerous cells (MCF-10A and peripheral blood mononuclear cells). Furthermore, significant induction of apoptosis and inhibition of epithelial-to-mesenchymal transition (EMT) and stemness were also observed in NMK-T-057-treated BC cells. The in silico study revealing the affinity of NMK-T-057 toward ␥-secretase was further validated by a fluorescence-based ␥-secretase activity assay, which confirmed inhibition of ␥-secretase activity in NMK-T-057-treated BC cells. Interestingly, it was observed that NMK-T-057 induced significant autophagic responses in BC cells, which led to apoptosis. Moreover, NMK-T-057 was found to inhibit tumor progression in a 4T1-BALB/c mouse model. Hence, it may be concluded that NMK-T-057 could be a potential drug candidate against BC that can trigger autophagymediated cell death by inhibiting ␥-secretase-mediated activation of Notch signaling. Breast cancer (BC) 6 is the most common cancer in women and accounts for almost 15% of all cancer-related deaths in This work was partially supported by a University with Potential for Excellence (UPE)-II grant from the Government of India (to G. C.). The authors declare that they have no conflicts of interest with the contents of this article. This article contains Figs. S1-S5 and Tables S1 and S2.

A new class of organosilicon-based radiosynthons, heteroaromatic silicon-fluoride acceptors, namely, HetSiFAs, that readily undergo isotope exchange with dry [18F]­fluoride at room temperature in high radiochemical yield (up to 94%) with good molar activity is reported. Radiofluorination proceeds in a single step in 2 min without high-performance liquid chromatography purification to provide an operationally simple method for 18F-PET tracer production. This method was used to prepare an 18F-labeled commercial tetrapeptide, and positron emission tomography imaging confirmed in vivo stability.