Welcome to the laboratory of Dr. Pedro Brugarolas at the Gordon Center for Medical Imaging of Massachusetts General Hospital and Harvard Medical School. The focus of our group is to develop new small molecule PET radioligands for neurological diseases and immunoPET. We are particularly interested in developing tracers for potassium channels in the brain to image demyelinating diseases (see Developing a PET tracer for K⁺ channels) and tracers for calcium channels to image neuropathic pain and epilepsy (see Developing PET tracers for Ca2+ channels).We are also interested in developing small molecules to image therapeutic monoclonal antibodies using a pretargeting approach (see PET-tag: a new approach to imaging monoclonal antibodies) and exploring new radiochemistry to make our tracers (see New fluorination and radiofluorination strategies). The lab is located in the historic Bulfinch building at MGH main campus only feet away from the GCMI cyclotron which produces 11C and 18F daily and the MGH animal facilities. The lab has state-of-the-art chemistry and radiochemistry equipment and access to small and large animal PET cameras as well as human PET scanners.
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Assistant Professor of Radiology 1/2018 - present
Harvard Medical School, Boston, Massachusetts
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This work is partially funded by the NIH/NINDS, the Polsky Center for Entrepreneurship and Innovation and an MGH ECOR Physician and/or Scientist Development Award to Dr. Ramos-Torres
Potassium (K⁺) channels in myelinated axons are normally buried beneath the myelin sheath. During MS and other demyelinating conditions such as traumatic brain injury and stroke, myelin becomes damaged leaving these channels exposed, which results in leakage of intracellular K⁺ ions and disruption of axonal conduction of action potentials. Consequently, K⁺ channel blockers, such as 4-aminopyridine, have been exploited clinically to enhance axonal conduction and improve neurological function in patients with MS. We recently showed that K⁺ channels can be targeted for imaging demyelinated lesions in animal models of demyelination and are currently evaluating this tracer in humans. See ClinicalTrials.gov record for more information.
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This work is funded by the NIH/NINDS and an MGH ECOR Postdoctaral FMD award to Dr. Zhou
Pain and seizure disorders affect millions of people worldwide.
Non-invasive imaging of these conditions is critical for their diagnosis and clinical management.
Current imaging methods use a combination of techniques including MRI, [18F]FDG PET and SPECT, which lack specificity.
One feature shared by pain and seizure disorders is that the expression of certain calcium (Ca2+) channels
is altered in the disease focus. As such, imaging the alpha2delta-1 subunit of voltage-dependent Ca2+ channels by PET
may provide a new window into the pathology.
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This work is funded by the NIH/NIBIB
Therapeutic monoclonal antibodies comprise a multibilion dollar market. Just like any other therapeutic, these drugs do not work for every patient. Data from clinical trials shows responses between 15% and 60% for most therapeutic antibodies. Recent studies suggest that localization of the antibody is a good predictor of response. In this project, we are trying to develop a new way to image monoclonal antibodies using small molecule PET radioligands.
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Due to their electron-rich aromatic structure nucleophilic fluorination of pyridines is challenging, especially at the meta position. Current strategies for radiofluorination ofter require difficult to make precursors. In this project, we discovered that pyridine N-oxides which are easy to make and often commercially available can be excellent precursors. Furthermore, fluorination occurs quickly at room temperature.
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Development of a PET radiotracer for alpha2delta-1 receptors to visualize and quantify neuropathic pain mechanisms. 10/2020 - 6/2022
New tools for imaging: diagnostics based on therapeutics. 7/2017 - 6/2020
NIH/NIBIB R00EB020075 (PI)
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Karla Ramos Torres, PhD Postdoctoral Fellow
PhD in Chemistry, University of California, Berkeley, CA, 2016
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Marc D. Normandin, PhD
Assistant Professor, Department of Radiology, GCMI, MGH
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January, 2018: Publication of Development of a PET radioligand for potassium channels to image CNS demyelination [press coverage] July, 2015: Announcement Innovation Fund award [read article] June, 2014: Presentation at the New York Academy of Sciences meeting: "Demyelination and Remyelination: From Mechanism to Therapy" (6/2014) [watch video] January, 2011: Interview by the National Multiple Sclerosis Society about our work [read transcript]
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22. Y.P. Zhou, K.J. Makaravage and P. Brugarolas*. Radiolabeling with [11C]HCN for positron emission tomography Nuclear Medicine and Biology 102-3:56-86 2021.21. N.J. Guehl, R. Neelamegam, Y. Zhou, S. Moon, M. Dhaynaut, G. El Fakhri, M.D. Normandin* and P. Brugarolas*. Radiochemical Synthesis and Evaluation in Nonhuman Primates of 3‑[11C]methoxy-4-aminopyridine: a novel PET tracer for Imaging Potassium Channels in the CNS. ACS Chemical Neuroscience 12(4):756-765 2021. 20. T.M. Shoup, A. Griciuc, M.D. Normandin, L. Quinti, L.V. Walsh, M. Dhaynaut, S. Moon, N.J. Guehl, P. Brugarolas, D.R. Elmaleh*, G. El Fakhri* and R.E. Tanzi. Evaluation of Fluorinated Cromolyn Derivatives as Potential Therapeutics for Alzheimer’s Disease. J. Alzheimer's Dis. 80(2):775-786 2021. 19. N.J. Guehl, K.M. Ramos-Torres, C. Linnman, S. Moon, M. Dhaynaut, M.Q. Wilks, P.K. Han, C. Ma, R. Neelamegam, Y. Zhou, B. Popko, J.A. Correia, D.S. Reich, G. El Fakhri, P. Herscovitch, M.D. Normandin* and P. Brugarolas*. Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques. J. Cereb. Blood Flow Metab. 41(7):1721-1733 2021. 18. K.M. Ramos-Torres, Y. Zhou, B. Yang, N.J. Guehl, S. Moon, S. Telu, M.D. Normandin, V.W Pike* and P Brugarolas*. Syntheses of [11C]2- and [11C]3-trifluoromethyl-4-aminopyridine: potential PET radioligands for demyelinating diseases. RSC Med. Chem. 11, 1161-1167 2020. 17. S. Foxley, G. Wildenberg, V. Sampathkumar, G.S. Karczmar, P. Brugarolas and N. Kasthuri. Sensitivity to myelin using model-free analysis of the water resonance line-shape in postmortem mouse brain. Magn. Reson. Imaging 85: 667–677 2020. 16. P. Brugarolas, J. Comstock, D.W. Dick, T. Ellmer, J.W Engle, S.E. Lapi, S.H. Liang, E.E. Parent, N.V.K. Pillarsetty, S. Selivanova, X. Sun, A. Vavere and P.J.H. Scott, SNMMI RPSC Council. Fifty Years of Radiopharmaceuticals. J. Nucl. Med. Technol. 48(Suppl 1), 34S-39S. 2020. 15. S. Rodríguez-Rangel, A.D.Bravin, K.M.Ramos-Torres, P.Brugarolas* and J.E.Sánchez-Rodríguez* Structure-activity relationship studies of four novel 4-aminopyridine K⁺ channel blockers. Sci. Rep. 10(1), 52. 2020. 14. P. Brugarolas*, D.S. Reich and B. Popko. Detecting Demyelination by PET: The Lesion as Imaging Target. Mol. Imaging, 17:1536012118785471, 2018. 13. B. Elbaz, J.D. Aaker, S. Isaac, A. Kolarzyk, P. Brugarolas, A. Eden and B. Popko* Phosphorylation State of ZFP24 Controls Oligodendrocyte Differentiation. Cell Rep. 23(8), 2254-2263, 2018 12. P. Brugarolas*, J.E. Sánchez-Rodríguez, H.M. Tsai, F. Basuli, S.H. Cheng, X. Zhang, A.V. Caprariello, J. Lacroix, R. Freifelder, D. Murali, O. DeJesus, R.H. Miller, R.E. Swenson, C.T. Chen, P. Herscovitch, D.S. Reich, F. Bezanilla and B. Popko.* Development of a PET radioligand for potassium channels to image CNS demyelination. Sci. Rep. 8, 607 2018. 11. F. Basuli*, X. Zhang, P. Brugarolas, D.S. Reich and R.E. Swenson. An efficient new method for the synthesis of [18F]3-fluoro-4-aminopyridine via Yamada-Curtius rearrangement. J. Labelled. Comp. Radiopharm. 61(2):112-1172018. 10. P. Brugarolas*, M. Bhuiyan, A. Kucharski and R. Freifelder. Automated radiochemical synthesis of [18F]3F4AP: a novel PET tracer for imaging demyelinating diseases. J. Vis. Exp. (123): 55537 2016. 9. P. Brugarolas*, R. Freifelder, S.-H. Cheng and O. DeJesus. Synthesis of meta-substituted [18F]3-fluoro-4-aminopyridine via direct radiofluorination of pyridine N-oxides. Chem. Commun. 52, 7150-2 2016.
8. S. Way, J. Podojil, B. Clayton, A. Zaremba, T. Collins, R. Kunjamma, A. Robinson, P. Brugarolas, R. Miller, S. Miller and B. Popko. Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic. Nat. Commun. 6, 6532, 2015.
7. P. Brugarolas and B. Popko. Remyelination therapy goes to trial for multiple sclerosis. Neurol. Neuroimmunol. Neuroinflamm. 1(2):e26, 2014.
6. Q. Ji, L. Zhang, M.B. Jones, F. Sun, X. Deng, H. Liang, H. Cho, P. Brugarolas, Y.N. Gao, S.N. Peterson, L. Lan, T. Bae and C. He. Molecular mechanism of quinone signaling mediated through S-quinonization of a YodB family repressor QsrR. Proc. Natl. Acad. Sci. U. S. A. 110(13):5010-5, 2013.
5. P. Brugarolas, F. Movahedzadeh, Y. Wang, N. Zhang, I.L. Bartek, Y.N. Gao, M.I. Voskuil, S.G. Franzblau and C. He. The oxidation-sensing regulator (MosR) is a new redox-dependent transcription factor in Mycobacterium tuberculosis. J. Biol. Chem. 287(45):37703-12, 2012.
4. B.P. Aryal, P. Brugarolas and C. He. Binding of ReO4 with an engineered MoO4-binding protein: towards a new approach in radiopharmaceutical applications. J. Biol. Inorg. Chem. 17(1):97-106, 2012.
3. P. Brugarolas, E.M. Duguid, W. Zhang, C.B. Poor and C. He. Structural and biochemical characterization of N5-carboxyaminoimidazole ribonucleotide synthetase and N5-carboxyaminoimidazole ribonucleotide mutase from Staphylococcus aureus. Acta Crystallogr. D Biol. Crystallogr. 67(8):707-15, 2011.
2. P.R. Chen, P. Brugarolas and C. He. Redox signaling in human pathogens. Antioxid. Redox Signal. 14(6):1107-18, 2011. Review.
1. J. García-Martínez, P. Brugarolas and S. Domínguez-Domínguez. Ordered circular mesoporosity induced by phospholipids. Micropor. Mesopor. Materials. 100(1-3): 63-69, 2007.
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2. U.S. Patent: US10160695B2. Synthesis of meta-substituted [18F]3-fluoro-4-aminopyridines by direct radiofluorination of pyridine n-oxides. Inventor: P. Brugarolas. Priority date 4/2016. [GooglePatents]
1. U.S. Patent: US9617215B2. Use of fluorinated derivatives of 4-aminopyridine in therapeutics and medical imaging. Inventors: P. Brugarolas, B. Popko, D. Appelbaum, C.T. Chen. Priority date 5/2012. [GooglePatents]
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13. Evaluation of the demyelination PET radiotracer [18F]3F4AP in rhesus macaque. BRAIN & BRAIN PET, Yokohama, Japan. July, 2019. (presented by M.D. Normandin)
12. Novel 11C-labeled tracer for potassium channels in the brain: synthesis and imaging in non-human primates. Society of Nuclear Medicine and Molecular Imaging Annual Meeting, Anaheim, CA. June, 2019.
11. Pharmacokinetic Characterization of [18F]3F4AP in non-human primates". Society of Nuclear Medicine and Molecular Imaging Annual Meeting, Anaheim, CA. June, 2019. (presented by N. Guehl)
10. Towards imaging multiple sclerosis by PET: development of a PET radiotracer for potassium channels for imaging demyelination. XII International Symposium of Functional Neuroreceptor Mapping of the Living Brain, London, UK. July, 2018
9. Evaluation of [18F]3F4AP in non-human primates: a PET tracer for potassium channels to image brain demyelination Society of Nuclear Medicine and Molecular Imaging Annual Meeting, Philadelphia, PA. June, 2018
8. Strategies for the radiochemical synthesis of [11C]2- and [11C]3-trifluoromethyl-4-aminopyridine: Potential radioligands for brain demyelination. 255th National Meeting American Chemical Society, New Orleans, LA. March, 2018
7. [18F]3F4AP: a novel PET tracer for demyelinating diseases. 2016 World Molecular Imaging Congress, New York, NY. September, 2016
6. Radiochemical synthesis of metafluorinated pyridines via direct nucleophilic fluorination of pyridine N-oxides: Synthesis of [18F]3-fluoro-4-aminopyridine. 252nd National Meeting American Chemical Society, Philadelphia, PA. August, 2016
5. [18F]3F4AP: a new PET tracer for brain demyelination. Society of Nuclear Medicine and Molecular Imaging Annual Meeting, San Diego, CA. June, 2016
4. Radiochemical synthesis of [18F]3-fluoro-4-aminopyridine: a case for producing metafluorinated pyridines via direct nucleophilic fluorination of pyridine N-oxides. Society of Nuclear Medicine and Molecular Imaging Annual Meeting, San Diego, CA. June, 2016
3. Fluorinated 4-aminopyrdines as PET tracers for MS. Society of Nuclear Medicine and Molecular Imaging Annual Meeting, Baltimore, MD. June, 2015
2. Fluorinated 4-aminopyrdines as PET tracers for MS. 248th National Meeting American Chemical Society, San Francisco, CA. August, 2014
1. Novel Tracer for Demyelination and Remyelination. Demyelination and Remyelination: From Mechanism to Therapy, New York Academy of Sciences, New York, NY. June, 2014 [watch video]
10/2020 "Development and translation of [18F]3F4AP: a novel PET tracer for demyelinating diseases”. Department of Radiology, Brigham and Women’s Hospital, Boston, MA.4/2020 "Developing PET radiotracers for visualizing brain demyelination and other pathological processes”. Department of Radiology, Weill Cornell Medicine, New York, NY. 1/2020 "Developing PET Radiotracers for Brain Injuries, Pain and Other Diseases”. Department of Radiology, The University of Chicago, Chicago, IL. 1/2017 "[18F]3F4AP: a new PET tracer for imaging brain demyelination”. Institute for Neurodegenerative Disorders, University of California, San Francisco, CA. 12/2016 “[18F]3F4AP: a novel PET tracer for imaging brain demyelination”. Gordon Center for Medical Imaging, Massachusetts General Hospital, Boston, MA. 11/2016 “[18F]3F4AP: a new PET tracer for imaging demyelinated diseases”. Department of Radiology, New York University Langone Medical Center, New York, NY. 11/2016 “[18F]3F4AP: a new PET tracer for imaging brain demyelination”. Department of Radiology, Northwestern University, Chicago, IL 10/2016 "[18F]3F4AP: a new PET tracer for imaging demyelinated diseases”. Integrative Biosciences Institute and Department of Chemistry, Wayne State University, Detroit, MI. 9/2016 “[18F]3F4AP: a new PET tracer for imaging the demyelinated brain”. Department of Radiology, UT Southwestern Medical Center, Dallas, TX. 8/2016 “[18F]3F4AP: a new PET tracer for imaging the demyelinated brain”. Department of Radiology and Imaging Sciences, Indiana Univ. School of Medicine. Indianapolis, IN. 6/2016 “[18F]3F4AP: a new PET tracer for imaging the demyelinated brain”. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. 6/2016 "[18F]3F4AP: a new PET tracer for imaging the demyelinated brain”. Molecular Imaging Center, Department of Radiology, USC Keck School of Medicine, University of Southern California, Los Angeles, CA. 2/2016 “Developing a PET tracer for brain demyelination.” The University of Chicago. (Neuroscience Postdoc Seminar Series) 10/2014 “Developing a radiodiagnostic tracer for multiple sclerosis.” Loyola Neuroscience Society. Loyola University. Chicago, IL. (Student Invited Seminar) 5/2013 “Aiming for the lesion: exploring new tracers and therapeutics specific for demyelinated axons.” The University of Chicago. (Neuroscience Translational Seminar) 2/2011 “MosR: a new redox sensor in Mtb.” Institute for Tuberculosis Research, University of Illinois at Chicago. (Invited Seminar Speaker)“Developing a radiodiagnostic tracer for multiple sclerosis.” Loyola Neuroscience Society. Loyola University. Chicago, IL. (Student Invited Seminar) 2/2011 “Us vs. Them. Exploring new strategies against bacteria.” Department of Chemistry, The University of Chicago. (Student Seminar Series)
Postdoc Opportunties Available!
Email Dr. Brugarolas with CV, letter describing research background and interests, and contact info of three references.
Pedro Brugarolas, PhD
Department of Radiology, Harvard Medical School
Gordon Center for Medical Imaging, Massachusetts General Hospital
55 Fruit St., Bulfinch 051
Boston, MA 02114
Tel. (617) 643-4574
E-mail: pbrugarolas AT mgh DOT harvard DOT edu