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

Fellows

    Students

      Research Assistants

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

        Collaborators

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

        Selected Publications

        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • Choi JK, Zhu A, Jenkins BG, Hattori S, Kil KE, Takagi T, Ishii S, Miyakawa T, Brownell AL. Combined behavioral studies and in vivo imaging of inflammatory response and expression of mGlu5 receptors in schnurri-2 knockout mice. Neurosci. Lett. 2015; 609():159-64
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • Brownell AL. Prognostic imaging of neuroblastoma. Eur. J. Nucl. Med. Mol. Imaging 2014; 41(6):1043-5
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • Black YD, Xiao D, Pellegrino D, Kachroo A, Brownell AL, Schwarzschild MA. Protective effect of metabotropic glutamate mGluR5 receptor elimination in a 6-hydroxydopamine model of Parkinson’s disease. Neurosci. Lett. 2010; 486(3):161-5
          View in: PubMed
        • Sanchez-Pernaute R, Wang JQ, Kuruppu D, Cao L, Tueckmantel W, Kozikowski A, Isacson O, Brownell AL. Enhanced binding of metabotropic glutamate receptor type 5 (mGluR5) PET tracers in the brain of parkinsonian primates. Neuroimage 2008; 42(1):248-51
          View in: PubMed
        • 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
          View in: PubMed
        • Cicchetti F, Gross RE, Bulte JW, Owen M, Chen I, Saint-Pierre M, Wang X, Yu M, Brownell AL. Dual-modality in vivo monitoring of subventricular zone stem cell migration and metabolism. Contrast Media Mol Imaging ; 2(3):130-8
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • Brownell AL, Livni E, Galpern W, Isacson O. In vivo PET imaging in rat of dopamine terminals reveals functional neural transplants. Ann. Neurol. 1998; 43(3):387-90
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed
        • 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
          View in: PubMed

         

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