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 a few feet away from the GCMI cyclotron which produces carbon-11 and fluorine-18 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 a K99 award from NIH/NIBIB 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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Can [18F]3F4AP detect brain demyelination? Evaluation of novel PET tracer in nonhuman primates and humans. 12/2019 - 11/2024
Development of a PET radiotracer for alpha2delta-1 receptors to visualize and quantify neuropathic pain mechanisms. 10/2020 - 5/2023
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Karla M. Ramos Torres, PhD Instructor
PhD in Chemistry, University of California, Berkeley, CA, 2016
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Marc D. Normandin, PhD
Associate 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] Jan., 2013: Interview by the National Multiple Sclerosis Society about our work [read transcript]
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31. Y. Sun, S. Rodriguez-Rangel, L. Zhang, J.E. Sanchez-Rodriguez* and P. Brugarolas*. Chemical and biophysical characterization of novel potassium channel blocker 3-fluoro-5-methylpyridin-4-amine. bioRxiv, DOI: 10.1101/2023.08.08.550404, 2023.30. Y.P. Zhou, M.Q. Wilks, M. Dhaynaut, N.J. Guehl, S.H. Moon, G. El Fakhri, M.D. Normandin* and P. Brugarolas*. Radiosynthesis automation, non-human primate biodistribution and dosimetry of K⁺ channel tracer [11C]3MeO4AP. bioRxiv, DOI: 10.1101/2023.03.28.534386, 2023.
29. Y. Zhou, M.D. Normandin, V. Belov,M.T. Macdonald-Soccorso, S.H. Moon, Y. Sun, G. El Fakhri, N.J. Guehl* and P. Brugarolas* Evaluation of trans- and cis-4-[18F]fluorogabapentin for brain PET imaging. ACS Chem. Neurosci., DOI: 10.1021/acschemneuro.3c00593 2023.28. Y. Sun, K.M. Ramos-Torres and P. Brugarolas*. Metabolic Stability of the Demyelination PET Tracer [18F]3F4AP and Identification of its Metabolites. J. Pharmacol. Exp. Ther. 386(1):93-101, 2023. 27. S. Telu*, S. Jana, M.B. Haskali, B.Y. Yang, J. Jakobsson, Q. Zhao, K.M. Ramos-Torres, P. Brugarolas and V.W Pike* Broad-scope syntheses of [11C/[11F] trifluoromethylarenes from aryl(mesityl)iodonium salts. Chem. Eur. J. 29, e202204004. 2023. 26. P. Brugarolas*, M.Q. Wilks, J. Noel, J.A. Kaiser, D.R. Vesper, K.M. Ramos-Torres, N.J. Guehl, M.T. Macdonald-Soccorso, Y. Sun, P.A. Rice, D.L. Yokell, R. Lim, M.D. Normandin and G. El Fakhri*. Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP. Eur. J. Nuc. Med. Mol. Imag. 50, 344-51, 2023. 25. Y. Sun, N.J. Guehl, Y.P. Zhou, V. Belov, K. Takahashi, M. Dhaynaut, S.H. Moon, G. El Fakhri, M.D. Normandin and P. Brugarolas*. Radiochemical Synthesis and Evaluation of 3-[11C]methyl-4-aminopyridine in Rodents and Non-Human Primates for Imaging Potassium Channels in the CNS. ACS Chem. Neurosci. 13, 23, 3342-51, 2022. 24. Y.P. Zhou, Y. Sun, K. Takahashi, V. Belov, N. Andrews, C.J. Woolf and P. Brugarolas*. Development of a PET radioligand for α2δ-1 subunit of calcium channels for imaging neuropathic pain. Eur. J. Med. Chem. 242:114688, 2022. 23. F.J. Detmer, N.M. Alpert, S.H. Moon, M. Dhaynaut, J.L. Guerrero, N.J. Guehl, F. Xing,P. Brugarolas, T.M. Shoup, M.D. Normandin, M. Pelletier-Galarneau, G. El Fakhri* and Y. Petibon*. PET imaging of mitochondrial function in acute doxorubicin-induced cardiotoxicity: a proof-of-principle study. Sci. Rep. 12:6122, 2022. 22. Y.P. Zhou, K.J. Makaravage and P. Brugarolas*. Radiolabeling with [11C]HCN for positron emission tomography. Nuc. Med. Biol. 102-3:56-86, 2021. 21. N.J. Guehl, R. Neelamegam, Y. Zhou, S.H. 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 Chem. Neurosci. 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):112-117, 2018. 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.
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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3. U.S. Patent Application: PCT/US2021/028455. Fluorinated derivatives of gabapentin and methods of use thereof. Inventor: P. Brugarolas, Y. Zhou. Priority date 4/2020. Patent Pending. [Patentscope]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. Licensed by Fuzionaire Diagnostics Dec. 2020. [GooglePatents]
1. U.S. Patents: US9617215B2 and US10442767B2. 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. Licensed by Fuzionaire Diagnostics Dec. 2020. [GooglePatents] [GooglePatents2]
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12/2022 "Development of PET radioligands for multiple sclerosis and other diseases”. Radiology Grand Rounds, University of Rochester School of Medicine, Rochester, NY.11/2022 "Making new PET tracers for brain imaging and developing new (radio)chemistry along the way”. Bilkent Chemistry Seminar Series, Chemistry Department, Bilkent University, Ankara, Turkey. 10/2022 "Development and evaluation of novel PET tracers for neurological diseases”. Global R&D Seminar, GE Healthcare. 10/2022 "4-aminopyridine: Performing New Tricks with an Old Drug”. Presentation for Myro Therapeutics, Boston, MA. 11/2021 "Development of PET radioligands for multiple sclerosis and other diseases”. Department of Nuclear Medicine, Clínica Universitaria de Navarra, Pamplona, Spain. 5/2021 "Development of PET radioligands for multiple sclerosis and other diseases”. Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden. 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.
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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