Brownell Lab

About the lab

PI: Anna-Liisa Brownell

The Brownell Lab research focuses on the glutamatergic system in the brain, as it relates to sensorimotor and cognitive problems. They are investigating PET ligands that can be used to aid in treatment development.

Research

Developing in vivo imaging ligands for metabotropic glutamate group II receptor (mGluR2)

Positive allosteric modulators of mGluR2 have therapeutic potential for a range of psychiatric and neurological disorders, but there is a need for methods, such as in vivo imaging, that can detect therapeutic response.

Developing mGlu4 PET imaging ligand for diagnostic purposes to support drug development and medical applications

Parkinson’s disease is a devastating neurodegenerative disorder and there is not yet cure for it. There are several theories of its pathology including modulation of dopamine and glutamate neurotransmission. In preclinical investigation mGlu4 positive allosteric modulators (PAMs) have demonstrated anti-parkinsonian effects making them a new therapeutic approach for PD and the first clinical trial of using mGlu4 PAM based drug is in process. 

Investigate mGluR5 function in different neurological conditions and disorders

The diversity and heterogeneous distribution of mGluR subtypes through the CNS provides an opportunity for developing compounds (or drugs) to selectively target a specific subsystem, aiming to ameliorate symptoms of distinct neurological disorders while limiting the disruptive effects of an altered glutamate transmission on brain function. In particular, mGlu5 receptors regulate local protein synthesis and mRNA translation at synapses, and are thus ideally positioned to control synaptic plasticity.  Studies have implicated mGlu5 in a wide variety of symptoms associated with Fragile X Syndrome (FXS). Finding translatable similarities between glutamatergic neurotransmission in FXS mice and human Fragile X Syndrome will help guide future clinical trials toward more successful outcomes and effective drugs for treatments.

Members

Faculty


Fellows


    Students


      Research Assistants


        • Darshini Kuruppu
        • Zhaoda Zhang
        • Chuzhi Pan
        • Sevda Lule

         

        Collaborators

        Ji-Kyung Choi, Maria Mody, Bruce Jenkins, Michael Whalen,

        Selected Publications

        • Wang J, Moon SH, Cleary MB, Shoup TM, El Fakhri G, Zhang Z, Brownell AL. Detailed radiosynthesis of [ F]mG4P027 as a positron emission tomography radiotracer for mGluR4. J Labelled Comp Radiopharm 2023 66 (2):34-40
        • Yuan G, Dhaynaut M, Guehl NJ, Neelamegam R, Moon SH, Qu X, Poutiainen P, Afshar S, Fakhri GE, Normandin MD, Brownell AL. PET imaging studies to investigate functional expression of mGluR2 using [C]mG2P001. J Cereb Blood Flow Metab 2023 43 (2):296-308
        • Yuan G, Dhaynaut M, Lan Y, Guehl NJ, Huynh D, Iyengar SM, Afshar S, Jain MK, Pickett JE, Kang HJ, Wang H, Moon SH, Ondrechen MJ, Wang C, Shoup TM, El Fakhri G, Normandin MD, Brownell AL. Synthesis and Characterization of 5-(2-Fluoro-4-[C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2-pyrano[2,3-]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2. J Med Chem 2022 ():
        • Mody M, Petibon Y, Han P, Kuruppu D, Ma C, Yokell D, Neelamegam R, Normandin MD, Fakhri GE, Brownell AL. In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker. Sci Rep 2021 11 (1):15897
        • Yuan G, Guehl NJ, Zheng B, Qu X, Moon SH, Dhaynaut M, Shoup TM, Afshar S, Kang HJ, Zhang Z, El Fakhri G, Normandin MD, Brownell AL. Synthesis and Characterization of [F]JNJ-46356479 as the First F-Labeled PET Imaging Ligand for Metabotropic Glutamate Receptor 2. Mol Imaging Biol 2021 23 (4):527-536
        • Yuan G, Shoup TM, Moon SH, Brownell AL. A concise method for fully automated radiosyntheses of [F]JNJ-46356479 and [F]FITM Cu-mediated F-fluorination of organoboranes. RSC Adv 2020 10 (42):25223-25227
        • Yuan G, Qu X, Zheng B, Neelamegam R, Afshar S, Iyengar S, Pan C, Wang J, Kang HJ, Ondrechen MJ, Poutiainen P, El Fakhri G, Zhang Z, Brownell AL. Design, Synthesis, and Characterization of Benzimidazole Derivatives as Positron Emission Tomography Imaging Ligands for Metabotropic Glutamate Receptor 2. J Med Chem 2020 63 (20):12060-12072
        • Wang J, Qu X, Shoup TM, Yuan G, Afshar S, Pan C, Zhu A, Choi JK, Kang HJ, Poutiainen P, El Fakhri G, Zhang Z, Brownell AL. Synthesis and Characterization of Fluorine-18-Labeled -(4-Chloro-3-((fluoromethyl-)thio)phenyl)picolinamide for Imaging of mGluR4 in Brain. J Med Chem 2020 63 (6):3381-3389
        • Poutiainen P, Jaronen M, Quintana FJ, Brownell AL. Precision Medicine in Multiple Sclerosis: Future of PET Imaging of Inflammation and Reactive Astrocytes. Front Mol Neurosci 2016 9 ():85
        • Kil KE, Poutiainen P, Zhang Z, Zhu A, Kuruppu D, Prabhakar S, Choi JK, Tannous BA, Brownell AL. Synthesis and evaluation of N-(methylthiophenyl)picolinamide derivatives as PET radioligands for metabotropic glutamate receptor subtype 4. Bioorg Med Chem Lett 2016 26 (1):133-9
        • Brownell AL, Kuruppu D, Kil KE, Jokivarsi K, Poutiainen P, Zhu A, Maxwell M. PET imaging studies show enhanced expression of mGluR5 and inflammatory response during progressive degeneration in ALS mouse model expressing SOD1-G93A gene. J Neuroinflammation 2015 12 ():217
        • Jenkins BG, Zhu A, Poutiainen P, Choi JK, Kil KE, Zhang Z, Kuruppu D, Aytan N, Dedeoglu A, Brownell AL. Functional modulation of G-protein coupled receptors during Parkinson disease-like neurodegeneration. Neuropharmacology 2016 108 ():462-73
        • Arsenault D, Coulombe K, Zhu A, Gong C, Kil KE, Choi JK, Poutiainen P, Brownell AL. Loss of Metabotropic Glutamate Receptor 5 Function on Peripheral Benzodiazepine Receptor in Mice Prenatally Exposed to LPS. PLoS One 2015 10 (11):e0142093
        • Zhang Z, Kil KE, Poutiainen P, Choi JK, Kang HJ, Huang XP, Roth BL, Brownell AL. Re-exploring the N-phenylpicolinamide derivatives to develop mGlu4 ligands with improved affinity and in vitro microsomal stability. Bioorg Med Chem Lett 2015 25 (18):3956-60
        • Poutiainen P, Kil KE, Zhang Z, Kuruppu D, Tannous B, Brownell AL. Co-operative binding assay for the characterization of mGlu4 allosteric modulators. Neuropharmacology 2015 97 ():142-8
        • Arsenault D, Zhu A, Gong C, Kil KE, Kura S, Choi JK, Brownell AL. Hypo-anxious phenotype of adolescent offspring prenatally exposed to LPS is associated with reduced mGluR5 expression in hippocampus. Open J Med Psychol 2014 3 (3):202-211
        • Kil KE, Poutiainen P, Zhang Z, Zhu A, Choi JK, Jokivarsi K, Brownell AL. Radiosynthesis and evaluation of an 18F-labeled positron emission tomography (PET) radioligand for metabotropic glutamate receptor subtype 4 (mGlu4). J Med Chem 2014 57 (21):9130-8
        • Kil KE, Zhu A, Zhang Z, Choi JK, Kura S, Gong C, Brownell AL. Development of [(123)I]IPEB and [(123)I]IMPEB as SPECT Radioligands for Metabotropic Glutamate Receptor Subtype 5. ACS Med Chem Lett 2014 5 (6):652-6
        • Brownell AL. Prognostic imaging of neuroblastoma. Eur J Nucl Med Mol Imaging 2014 41 (6):1043-5
        • Kil KE, Zhang Z, Jokivarsi K, Gong C, Choi JK, Kura S, Brownell AL. Radiosynthesis of N-(4-chloro-3-[(11)C]methoxyphenyl)-2-picolinamide ([(11)C]ML128) as a PET radiotracer for metabotropic glutamate receptor subtype 4 (mGlu4). Bioorg Med Chem 2013 21 (19):5955-62
        • Wang JQ, Zhang Z, Kuruppu D, Brownell AL. Radiosynthesis of PET radiotracer as a prodrug for imaging group II metabotropic glutamate receptors in vivo. Bioorg Med Chem Lett 2012 22 (5):1958-62
        • Wang JQ, Tueckmantel W, Zhu A, Pellegrino D, Brownell AL. Synthesis and preliminary biological evaluation of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile as a PET radiotracer for imaging metabotropic glutamate receptor subtype 5. Synapse 2007 61 (12):951-61
        • Pellegrino D, Cicchetti F, Wang X, Zhu A, Yu M, Saint-Pierre M, Brownell AL. Modulation of dopaminergic and glutamatergic brain function: PET studies on parkinsonian rats. J Nucl Med 2007 48 (7):1147-53
        • Zhu A, Wang X, Yu M, Wang JQ, Brownell AL. Evaluation of four pyridine analogs to characterize 6-OHDA-induced modulation of mGluR5 function in rat brain using microPET studies. J Cereb Blood Flow Metab 2007 27 (9):1623-31
        • Yu M, Tueckmantel W, Wang X, Zhu A, Kozikowski AP, Brownell AL. Methoxyphenylethynyl, methoxypyridylethynyl and phenylethynyl derivatives of pyridine: synthesis, radiolabeling and evaluation of new PET ligands for metabotropic glutamate subtype 5 receptors. Nucl Med Biol 2005 32 (6):631-40
        • Wang X, Sarkar A, Cicchetti F, Yu M, Zhu A, Jokivarsi K, Saint-Pierre M, Brownell AL. Cerebral PET imaging and histological evidence of transglutaminase inhibitor cystamine induced neuroprotection in transgenic R6/2 mouse model of Huntington’s disease. J Neurol Sci 2005 231 (1-2):57-66
        • Brownell AL, Chen YI, Yu M, Wang X, Dedeoglu A, Cicchetti F, Jenkins BG, Beal MF. 3-Nitropropionic acid-induced neurotoxicity–assessed by ultra high resolution positron emission tomography with comparison to magnetic resonance spectroscopy. J Neurochem 2004 89 (5):1206-14
        • Brownell AL, Canales K, Chen YI, Jenkins BG, Owen C, Livni E, Yu M, Cicchetti F, Sanchez-Pernaute R, Isacson O. Mapping of brain function after MPTP-induced neurotoxicity in a primate Parkinson’s disease model. Neuroimage 2003 20 (2):1064-75
        • Yu M, Någren K, Chen YI, Livni E, Elmaleh D, Kozikowski A, Wang X, Jokivarsi K, Brownell AL. Radiolabeling and biodistribution of methyl 2-(methoxycarbonyl)-2-(methylamino) bicyclo[2.1.1] -hexane -5-carboxylate, a potential neuroprotective drug. Life Sci 2003 73 (12):1577-85
        • Brownell AL, Jenkins BG, Isacson O. Dopamine imaging markers and predictive mathematical models for progressive degeneration in Parkinson’s disease. Biomed Pharmacother 1999 53 (3):131-40
        • Brownell AL, Jenkins BG, Elmaleh DR, Deacon TW, Spealman RD, Isacson O. Combined PET/MRS brain studies show dynamic and long-term physiological changes in a primate model of Parkinson disease. Nat Med 1998 4 (11):1308-12
        • Brownell AL, Elmaleh DR, Meltzer PC, Shoup TM, Brownell GL, Fischman AJ, Madras BK. Cocaine congeners as PET imaging probes for dopamine terminals. J Nucl Med 1996 37 (7):1186-92
        • Brownell AL, Hantraye P, Wullner U, Hamberg L, Shoup T, Elmaleh DR, Frim DM, Madras BK, Brownell GL, Rosen BR. PET- and MRI-based assessment of glucose utilization, dopamine receptor binding, and hemodynamic changes after lesions to the caudate-putamen in primates. Exp Neurol 1994 125 (1):41-51
        • Brownell AL, Kano M, McKinstry RC, Moskowitz MA, Rosen BR, Brownell GL. PET and MR studies of experimental focal stroke. J Comput Assist Tomogr 15 (3):376-80

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