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A four-step protocol for the synthesis of pyrazolo[1,5-a]pyrazines has been developed. Commercially available pyrazoles were alkylated and formylated in a regiocontrolled manner to give pyrazole-5-aldehydes bearing 2,2-dialkoxyethyl substitution on N-1. Efficient conditions for the subsequent deprotection and cyclization of these intermediates allowed access to pyrazolo[1,5-a]pyrazines with multiple substitution patterns. The versatility of the pyrazole-5-aldehyde intermediates was further demonstrated through a deprotection and double-reductive amination sequence to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazines. [ABSTRACT FROM AUTHOR]

A two-stepprotocol has been developed for the introduction ofcyanomethylene groups to metalated aromatics through the intermediacyof substituted isoxazoles. Apalladium-mediated cross-coupling reaction was used to introduce theisoxazole unit, followed by release of the cyanomethylene functionunder thermal or microwave-assisted conditions. The intermediate isoxazoleswere shown to be amenable to further functionalization prior to deprotectionof the sensitive cyanomethylene motif, allowing access to a wide rangeof aryl- and heteroaryl-substituted acetonitrile building blocks. [ABSTRACT FROM AUTHOR]

A copper-mediated method for the transformation of diverse arylboron compounds and arylstannanes to aryl-[11C]-nitriles is reported. This method is operationally simple, uses commercially available reagents, and is compatible with a wide variety of substituted aryl- and heteroaryl substrates. This method is applied to the automated synthesis of high specific activity [11C]perampanel in 10% nondecay-corrected radiochemical yield (RCY). [ABSTRACT FROM AUTHOR]

Changes in expression and dysfunctional signaling of TrkA/B/C receptors and oncogenic Trk fusion proteins are found in neurological diseases and cancers. Here, we describe the development of a first 18F-labeled optimized lead suitable for in vivo imaging of Trk, [18F]TRACK, which is radiosynthesized with ease from a nonactivated aryl precursor concurrently combining largely reduced P-gp liability and improved brain kinetics compared to previous leads while displaying high on-target affinity and human kinome selectivity. [ABSTRACT FROM AUTHOR]

This communication describes a method for the nucleophilic radiofluorination of electron-rich arenes. The reaction involves the initial C(sp²)-H functionalization of an electron-rich arene with MesI(OH)OTs to form a (mesityl)(aryl)iodonium salt. This salt is then used in situ in a Cu-mediated radiofluorination with [18F]KF. This approach leverages the stability and availability of electron-rich arene starting materials to enable mild late-stage radiofluorination of toluene, anisole, aniline, pyrrole, and thiophene derivatives. The radiofluorination has been automated to access a 41 mCi dose of an 18F-labeled nimesulide derivative in high (2800 ± 700 Ci/mmol) specific activity. [ABSTRACT FROM AUTHOR]

A copper-mediated nucleophilic radiofluorination of aryl- and vinylstannanes with [18F]KF is described. This method is fast, uses commercially available reagents, and is compatible with both electron-rich and electron-deficient arene substrates. This method has been applied to the manual synthesis of a variety of clinically relevant radiotracers including protected [18F]F-phenylalanine and [18F]F-DOPA. In addition, an automated synthesis of [18F]MPPF is demonstrated that delivers a clinically validated dose of 200 ± 20 mCi with a high specific activity of 2400 ± 900 Ci/mmol. [ABSTRACT FROM AUTHOR]

A copper-mediated radiofluorination of aryl- and vinylboronic acids with K18F is described. This method exhibits high functional group tolerance and is effective for the radiofluorination of a range of electron-deficient, -neutral, and -rich aryl-, heteroaryl-, and vinylboronic acids. This method has been applied to the synthesis of [18F]FPEB, a PET radiotracer for quantifying metabotropic glutamate 5 receptors. [ABSTRACT FROM AUTHOR]

Stereochemistry is a very important issue for the pharmaceutical industry and can determine drug efficacy. The design and synthesis of small molecules, especially chiral molecules, which selectively target and inhibit amyloid-β-(Aβ) aggregation, represent valid therapeutic strategies for treatment of Alzheimer’s disease (AD). Herein we report that two triplehelical dinuclear metallosupramolecular complexes can act as a novel class of chiral amyloid-/βinhibitors. Through targeting α /β-discordant stretches at the early steps of aggregation, these metal complexes can enantioselectively inhibit A/β aggregation, which is demonstrated using fluorescent living cell-based screening and multiple biophysical and biochemical approaches. To the best of our knowledge, this is the first report of enantioselective inhibition of A/β aggregation. Intriguingly, as a promising candidate for AD treatment, the chiral metal complex can cross the blood-brain barrier and have superoxide dismutase activity. It is well-known that chiral discrimination is important for understanding chiral drug action. Generally, one enantiomer is pharmaceutically active while the other is inactive or exerts severe side effects. Chiral discrimination should be important for AD treatment. Our work provides new insights into chiral inhibition of A/β aggregation and opens a new avenue for design and screening of chiral agents as A/β inhibitors against AD. [ABSTRACT FROM AUTHOR]