Pedro Brugarolas | Gordon Center for Medical Imaging

Welcome to the Brugarolas lab

PEDRO BRUGAROLAS - RESEARCH - FUNDING - LAB MEMBERS - COLLABORATORS - NEWS - PUBLICATIONS - OPPORTUNITIES - CONTACT

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 brain disorders and immunoPET. We are particularly interested in developing tracers for potassium channels in the brain to image multiple sclerosis (see Developing a PET tracer for K⁺ channels) and tracers for calcium channels to image epilepsy and pain (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 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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PEDRO BRUGAROLAS

Assistant Professor, Department of Radiology, Harvard Medical School 1/2018 - present
Massachusetts General Hospital, Boston, Massachusetts

Assistant Investigator, Gordon Center for Medical Imaging 7/2018 - present
Massachusetts General Hospital, Boston, Massachusetts

Visiting Scientist, Radiochemistry 3/2017 - 6/2017
Mentor Victor W. Pike, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

Postdoc, Neuroscience and PET 1/2012 - 2/2017
Mentor Brian Popko, Department of Neurology, The University of Chicago, Chicago, Illinois

Ph.D. in Chemistry 9/2006 - 12/2011
Advisor Chuan He, Department of Chemistry, The University of Chicago, Chicago, Illinois

B.E. in Computer Science 12/2008
Universidad Nacional de Educacion a Distancia - UNED, Madrid, Spain

B.S. in Chemistry 6/2005
University of Alicante, Alicante, Spain

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RESEARCH SUMMARY

1. DEVELOPING A PET TRACER FOR POTASSIUM CHANNELS

This work is funded by the funded by the Polsky Center for Entrepreneurship and Innovation

Potassium (K⁺) channels in myelinated axons are normally buried beneath the myelin sheath. During MS and other demyelinating conditions, 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 MS and are working to translate this technology to humans.

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2. DEVELOPING PET TRACERS FOR CALCIUM CHANNELS

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 calcium (Ca2+) channels is altered in the disease focus. As such, imaging Ca2+ by PET may provide a new window the pathology.

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3. DEVELOPING A NON-COVALENT PRETARGETING APPROACH TO IMMUNO PET

This work is funded by the 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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4. NEW FLUORINATION AND RADIOFLUORINATION STRATEGIES

Due to their electron rich aromatic structure nucleophilic fluorination of pyridines is challenging, specially 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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FUNDING AND AWARDS

R00 Pathway to Independence Award (PI) 9/2017 - 6/2020
NIH/NIBIB

K99 Pathway to Independence Award (PI) 7/2015 - 6/2017
NIH/NIBIB

Innovation Fund Award (co-leader with B. Popko) 7/2015 - completion of goals
Polsky Center for Entrepreneurship and Innovation [read project summary]

R21 Exploratory/Developmental Research Award (co-investigator, PI: B. Popko) 2/2014 - 1/2016
NIH/NINDS

NMSS Pilot Research Award (co-investigator, PI: B. Popko) 10/2012 - 9/2013
National Multiple Sclerosis Society - Illinois Chapter

Graduate Fellowship 9/2006 - 8/2008
Fundación Caja Madrid, Madrid, Spain

McCormick Fellowship 9/2006 - 8/2008
The University of Chicago, Department of Chemistry

Undergraduate Research Fellowship 2004 - 2005
Spanish Ministry of Science and Education

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LAB MEMBERS

Karla Ramos Torres, PhD Postdoctoral Fellow
PhD in Chemistry, University of California, Berkeley, 2016

Yu-Peng Zhou, PhD Postdoctoral Fellow
PhD in Chemistry, Technische Universität Berline, Berlin, Germany, 2018

Alyssa D. Bravin Undergraduate Researcher
Harvard College, Class of 2020

Humra Athar, PhD Research Associate and Lab Manager
PhD in Biochemistry, Aligarh M University, Aligarh, India, 1999

Ramesh Neelamegam, PhD Instructor, PET Core Chemist
PhD in Organic Chemistry, University of Madras, India, 2008

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COLLABORATORS

Eric C. Klawiter, MD
Director, Multiple Sclerosis and Neuromyelitis Optica Unit
Assistant Professor, Department of Neurology, MGH

Sydney S. Cash, MD, PhD
Epileptologist, Associate Professor, Department of Neurology, MGH

Anna-Liisa Brownell, PhD
Professor, Department of Radiology, GCMI, MGH

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NEWS

Publication of Development of a PET radioligand for potassium channels to image CNS demyelination (1/2018)
[Press]

Announcement Innovation Fund award (7/7/2015) [read article]

Presentation at the New York Academy of Sciences meeting: "Demyelination and Remyelination: From Mechanism to Therapy" (6/2014) [watch video]

Interview by the National Multiple Sclerosis Society about our work (1/2013) [read article]

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PUBLICATIONS

14. P. Brugarolas*, D.S. Reich, B. Popko. Detecting Demyelination by PET: The Lesion as Imaging Target. Mol. Imaging, 17:1536012118785471, 2018 (*corresponding authors).

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 (*corresponding authors).

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. doi: 10.1002/jlcr 2017

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 (*corresponding author).

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 (*corresponding author).

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, Article number: 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. 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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PATENTS

2. U.S. Patent Application No. 15/497,747. 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. Utility Patent Application No. 13/329,597, European Patent Application No. 13791136.8EPO, Australian Patent Application No. 2013262578, Canadian Patent Application No. 2,911,307. 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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CONFERENCE ORAL PRESENTATIONS

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, 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, March, 2018

7. [18F]3F4AP: a novel PET tracer for demyelinating diseases. 2016 World Molecular Imaging Congress, New York, 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, August, 2016

5. [18F]3F4AP: a new PET tracer for brain demyelination. Society of Nuclear Medicine and Molecular Imaging Annual Meeting, San Diego, 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, June, 2016

3. Fluorinated 4-aminopyrdines as PET tracers for MS. Society of Nuclear Medicine and Molecular Imaging Annual Meeting, Baltimore, June, 2015

2. Fluorinated 4-aminopyrdines as PET tracers for MS. 248th National Meeting American Chemical Society, San Francisco, August, 2014

1. Novel Tracer for Demyelination and Remyelination. Demyelination and Remyelination: From Mechanism to Therapy, New York Academy of Sciences, June, 2014 [watch video]

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INVITED LECTURES

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)

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OPPORTUNITIES

Postdoc Opportunties Available!
Email PI with CV, letter describing research background and interests, and contact info of three recommenders.

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CONTACT INFORMATION

Pedro Brugarolas, PhD
Assistant Professor
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

Updated 8/10/2018