In This Issue Cite This: ACS Chem. Neurosci. 2017, 8, 2350-2351
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CROSSING THE BLOOD-BRAIN BARRIER
inflammatory diseases, such as arthritis and neuropathic pain. Much effort has been put forth in the design of P2X7R antagonists; however, few have progressed to clinical trials. One such class of antagonists, carboxamides initially reported by AstraZeneca, displayed potent inhibition in vitro but failed in vivo due to poor metabolic stability. One series in this library, derived from adamantanyl benzamide, is the focus of the study in this issue by Wilkinson et al. (DOI: 10.1021/acschemneuro.7b00272). Here, the authors report a detailed structure−activity relationship study of the adamantanyl benzamide series with the goal of improving the physicochemical and metabolic properties. Rather than modify the adamantane cage structure, which has been shown to be essential for potency, the authors explored substitution of the aryl group with heteroaromatic analogues. Another set of bioisosteres was synthesized, wherein the adamantane cage was systematically fluorinated. In total, 11 compounds were analyzed for trends in lipophilicity, uptake, binding affinity, and hP2X7R activity. It was found that the introduction of heteroaromatic moieties, which reduced the overall lipophilicity of the compound, did not perform any better than the benzamide parent compound. Trifluorination of the adamatane cage, however, improved the half-life of the antagonists in in vivo studies and also effectively hindered the metabolic pathway of the parent compounds, resulting in metabolically more stable compounds.
The ability to cross the blood-brain barrier (BBB) is critical for the delivery of drugs and imaging agents, such as PET radiotracers, to the brain. Yet the development of chemical agents that can successfully cross the BBB remains a major challenge, and can hinder the design of new radiotracer ligands that must comply with other chemical criteria for successful PET imaging. Methods that facilitate crossing the BBB pave the way for exciting opportunities in the development of new radiotracers that can be evaluated in vivo. In this issue, Gourand and co-workers (DOI: 10.1021/ acschemneuro.7b00218) describe a new method for delivery of the [18F]FLT (3′-deoxy-3′-18F-fluoro-l-thymidine) radiotracer, used for PET imaging of brain tumors, across the BBB and into brain tissue. [18F]FLT can easily cross the BBB on its own to image late-stage and high-grade tumors, as the BBB has deteriorated at these stages of brain cancer. However, to image early stage and low-grade tumors, FLT must be able to cross an intact BBB, which it cannot do on its own. Here, the authors link FLT to a redox chemical delivery system (CDS), consisting of a lipophilic 1,4-dihydropyridine. The lipophilicity of the CDS facilitates passage through the BBB by passive diffusion, while the 1,4-dihydropyridine moiety is subsequently enzymatically oxidized to release FLT. In this approach, FLT was conjugated to a [11C]-radiolabeled CDS, and the conjugate was tested for efficacy in rats. A set of four chemically distinct 1,4dihydroquinoline-based CDS [11C] compounds were prepared and analyzed in vivo, revealing high permeability across intact BBB and rapid oxidation of the CDS to afford fast release of FLT.
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IMPROVING METABOLIC STABILITY THROUGH FLUORINATION
CHEMICALLY MODIFIED RNA APTAMERS
RNA aptamers as therapeutics are a promising alternative to small molecules, due to their selectivity, water-solubility, and high potency. However, a major limitation of RNA aptamers is the inherent instability of the RNAs in vivo, as they are readily degraded by highly abundant ribonuclease enzymes. Chemical modifications to the RNA backbone, such as substitution of the 2′-hydroxyl group of the ribose sugar with a 2′-fluoro moiety, can confer protection from ribonuclease activity and dramatically increase the half-life of RNA in vivo. RNA aptamers are highly selective for their targets, and this selectivity is achieved through systematic evolution of ligands by exponential enrichment (SELEX). However, identification
The P2X7 purinoreceptor (P2X7R), a nonselective ligand-gated ion channel in the CNS, is upregulated by proinflammatory stimuli and when activated will release proinflammatory cytokines. It has been shown previously that inhibition of P2X7R results in reduction of symptoms in several neuro© 2017 American Chemical Society
pubs.acs.org/chemneuro
Published: November 15, 2017 2350
DOI: 10.1021/acschemneuro.7b00417 ACS Chem. Neurosci. 2017, 8, 2350−2351
ACS Chemical Neuroscience
In This Issue
of an RNA aptamer sequence followed by chemical modification to improve stability could fundamentally alter the structure of the aptamer, reducing its affinity for its target. In this issue, Huang and co-workers (DOI: 10.1021/ acschemneuro.7b00211) isolate a 2′-fluoro modified RNA aptamer by performing SELEX on a library of alreadychemically modified RNA sequences. The aptamer, which was isolated in both full-length (101 nucleotides) and truncated (69 nucleotides) forms, displays inhibitory activity against several glutamate receptor subtypes with a half-life of at least 2 days in serum.
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DOI: 10.1021/acschemneuro.7b00417 ACS Chem. Neurosci. 2017, 8, 2350−2351
