- Amide synthesis: Via nickel-catalysed reductive aminocarbonylation of aryl halides with nitroarenes
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Aminocarbonylation of aryl halides is one of the most useful methods in amide synthesis, but nitroarenes have not been used as a nitrogen source in this method even though they are more economical and accessible than anilines. Reported here is the development of nickel catalysis for the first three-component reactions of aryl halides, Co2(CO)8, and nitroarenes under reductive conditions to produce aryl amides. A wide range of (hetero)aryl iodides and bromides as well as nitro(hetero)arenes are suitable reaction partners, and high functional group compatibility has been achieved. The method might be used for the streamlined synthesis of aryl amides.
- Cheung, Chi Wai,Leendert Ploeger, Marten,Hu, Xile
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p. 655 - 659
(2018/01/28)
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- Re-exploring the N-phenylpicolinamide derivatives to develop mGlu4 ligands with improved affinity and in vitro microsomal stability
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Abstract In recent years, mGlu4 has received great attention and research effort because of the potential benefits of mGlu4 activation in treating numerous brain disorders, such as Parkinson's disease (PD). Many positive allosteric m
- Zhang, Zhaoda,Kil, Kun-Eek,Poutiainen, Pekka,Choi, Ji-Kyung,Kang, Hye-Jin,Huang, Xi-Ping,Roth, Bryan L.,Brownell, Anna-Liisa
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supporting information
p. 3956 - 3960
(2015/08/24)
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- Radiosynthesis of N-(4-chloro-3-[11C]methoxyphenyl)-2- picolinamide ([11C]ML128) as a PET radiotracer for metabotropic glutamate receptor subtype 4 (mGlu4)
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N-(Chloro-3-methoxyphenyl)-2-picolinamide (3, ML128, VU0361737) is an mGlu4 positive allosteric modulator (PAM), which is potent and centrally penetrating. 3 is also the first mGlu4 PAM to show efficacy in a preclinical Parkinson disease model upon systemic dosing. As a noninvasive medical imaging technique and a powerful tool in neurological research, positron emission tomography (PET) offers a possibility to investigate mGlu 4 expression in vivo under physiologic and pathological conditions. We synthesized a carbon-11 labeled ML128 ([11C]3) as a PET radiotracer for mGlu4, and characterized its biological properties in Sprague Dawley rats. [11C]3 was synthesized from N-(4-chloro-3-hydroxyphenyl)-2-picolinamide (2) using [11C]CH 3I. Total synthesis time was 38 ± 2.2 min (n = 7) from the end of bombardment to the formulation. The radioligand [11C]3 was obtained in 27.7 ± 5.3% (n = 5) decay corrected radiochemical yield based on the radioactivity of [11C]CO2. The radiochemical purity of [11C]3 was >99%. Specific activity was 188.7 ± 88.8 GBq/mol (n = 4) at the end of synthesis (EOS). PET images were conducted in 20 normal male Sprague Dawley rats including 11 control studies, 6 studies blocking with an mGlu4 modulator (4) to investigate specificity and 3 studies blocking with an mGlu5 modulator (MTEP) to investigate selectivity. These studies showed fast accumulation of [11C]3 (peak activity between 1-3 min) in several brain areas including striatum, thalamus, hippocampus, cerebellum, and olfactory bulb following with fast washout. Blocking studies with the mGlu4 modulator 4 showed 22-28% decrease of [11C]3 accumulation while studies of selectivity showed only minor decrease supporting good selectivity over mGlu5. Biodistribution studies and blood analyses support fast metabolism. Altogether this is the first PET imaging ligand for mGlu4, in which the labeled ML128 was used for imaging its in vivo distribution and pharmacokinetics in brain.
- Kil, Kun-Eek,Zhang, Zhaoda,Jokivarsi, Kimmo,Gong, Chunyu,Choi, Ji-Kyung,Kura, Sreekanth,Brownell, Anna-Liisa
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p. 5955 - 5962
(2013/09/23)
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- Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs)
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We report the synthesis and evaluation of a series of heterobiaryl amides as positive allosteric modulators of mGluR4. Compounds 9b and 9c showed submicromolar potency at both human and rat mGluR4. In addition, both 9b and 9c were shown to be centrally pe
- Engers, Darren W.,Niswender, Colleen M.,Weaver, C. David,Jadhav, Satyawan,Menon, Usha N.,Zamorano, Rocio,Conn, P. Jeffrey,Lindsley, Craig W.,Hopkins, Corey R.
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supporting information; experimental part
p. 4115 - 4118
(2010/01/16)
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