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Molecular Imaging Branch

Current Research

The Section on PET Neuroimaging Sciences develops and uses positron emission tomographic (PET) radioligands to study pathophysiology in several neuropsychiatric disorders. We use in vivo imaging to evaluate novel PET radioligands, first in animals, then in healthy human subjects, and finally in patients. Our current research focuses on two broad areas of study: neuroinflammation and cyclic adenosine monophosphate (cAMP) signaling.

2020 Publications

L. Cai, J.-S. Liow, C.L. Morse, S. Telu, R. Davies, M.P. Frankland, S.S. Zoghbi, K. Cheng, M.D. Hall, R.B. Innis, and V.W. Pike. Evaluation of [11C]NR2B-SMe and its enantiomers as radioligands for imaging the NR2B subunit within the NMDA receptor complex in rats. J. Nucl. Med. Jan 10, 2020 [epub ahead of print] doi: 10.2967/jnumed.119.235143.

G.M. Knudsen, 42 middle authors, and R.B. Innis. Guidelines for the content and format of PET brain data in publications and archives: A consensus paper. J. Cereb. Blood Flow Metab. Feb 17, 2020 [epub ahead of print] doi: 10.117/0271678X20905433.

J.-H. Lee, J.-S. Liow, S. Paul, C.L. Morse, M.B. Haskali, L. Manly, S. Shcherbinin, J.C. Ruble, N. Kant, E.C. Collins, H.N. Nuthall, P. Zanotti-Fregonara, S.S. Zoghbi, V.W. Pike, and R.B. Innis. PET quantification of brain O-GlcNAcase with [18F]LSN3316612 in healthy human volunteers EJNMMI Research. March 14, 2020 [epub ahead of print] doi:10.1186/s13550-020-0616-4.

Y. Wakabayashi, S. Telu, R.M. Dick, M. Fujita, M. Ooms, C.L. Morse, J.-S. Liow, J.S. Hong, R.L. Gladding, L.S. Manly, S.S. Zoghbi, X. Mo, E.C. D’Amato, J.A. Sindac, R.A. Nugent, B.E. Marron, M.E. Gurney, R.B. Innis, and V.W. Pike. Discovery, radiolabeling, and evaluation of subtype-selective inhibitors for positron emission tomography imaging of brain phosphodiesterase-4D. ACS Chem. Neurosci. April 8, 2020 [epub ahead of print] doi: 10.1021/acschemneuro.0c00077

L.D. Weidner, Y. Wakabayashi, L.A. Stolz, M.T. Collins, L. Guthrie, M. Victorino, J. Chung, W. Miller, S.S. Zoghbi, V.W. Pike, M. Fujita, R.B. Innis, and A.M. Boyce. PET imaging of phosphodiesterase-4 identifies affected dysplastic bone in McCune-Albright syndrome, a genetic mosaic disorder. J. Nucl. Med. April 13, 2020 [epub ahead of print] doi: 10.2967/jnumed.120.241976.

S. Shrestha, M.-J. Kim, M. Eldridge, M.L. Lehmann, M. Frankland, J.-S. Liow, Z.-X. Yu, M. Cortes-Salve, S. Telu, I.D. Henter, E. Gallagher, J.-H. Lee, J.M. Fredericks, C. Poffenberger, G. Tye, Y. Ruiz-Perdomo, F. Juarez Anaya, J.A. Montero Santamaria, R.L. Gladding, S.S. Zoghbi, M. Fujita, J.D. Katz, V.W. Pike, and R.B. Innis. PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study. J. Neuroinflammation. In press.

J. Meyer, S. Cervenka, M.-J. Kim, W.C. Kreisl, I.D. Henter, and R.B. Innis. Neuroinflammation in psychiatric disorders: PET imaging and promising new targets. Lancet Psychiatry. In press.

S.Lu, M.B. Haskali, K.M. Ruley, N.J.-F. Dreyfus, S.L. DuBois, S. Paul, J.-S. Liow, C.L. Morse, A. Kowalski, R.L. Gladding, J. Gilmore, A.J. Mogg, S.M. Morin, P.J. Lindsay-Scott, J.C. Ruble, N.A. Kant, S. Shcherbinin, V.N. Barth, M.P. Johnson, M. Cuadrado, E. Jambrina, A.J. Mannes, H.N. Nuthall, S.S. Zoghbi, C.D. Jesudason, R.B. Innis, and V.W. Pike.  PET ligands [18F]LSN3316612 and [11C]LSN3316612 quantify O-linked-B-N-acetyl-glucosamine hydrolase in the brain. Science Translational Medicine. In press.

M.-J. Kim, J.-H. Lee, F. Juarez Anaya, J. Hong, W. Miller, S. Telu, P. Singh, M.Y. Cortes, K. Henry, G.L. Tye, F.P. Frankland, J.A. Montero Santamaria, J.-S. Liow, S.S. Zoghbi, M. Fujita, V.W. Pike, and R.B. Innis. First-in human evaluation of [11C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in brain. EJNMMI. In press.



PET has unsurpassed sensitivity to localize and quantify specific proteins in the living brain that are hypothesized to underlie the pathophysiology of mental illnesses. Although PET has promising performance characteristics for research, the global results to date have had limited impact on our knowledge of the pathophysiology of mental disorders, and almost no impact on their treatment. Reasons for this limited impact include a relative paucity of radioligands compared to the large number of potential protein targets in brain, as well as a dearth of research trying to link PET to early treatment studies of psychiatric illnesses. Thus, three urgent needs exist as regards such research: 1) to develop new PET radioligands that can be used to determine molecular abnormalities underlying a variety of mental disorders; 2) to assess the practical utility of these radioligands in patient populations; and 3) to meaningfully use these radioligands in experimental medicine studies—e.g., proof-of-concept and proof-of-mechanism. In general, my laboratory has focused on developing radioligands and applying these radioligands in patient populations. In recent years, however, we have also sought to link newly developed radioligands to early therapeutic trials of experimental medicines. Towards this end, the two major targets currently being investigated in my laboratory are neuroinflammation and cyclic adenosine monophosphate (cAMP) signaling, indirectly assessed by imaging phosphodiesterase-4 (PDE4).

Project 1: Neuroinflammation and TSPO

Translocator protein (TSPO) is a mitochondrial protein that is highly expressed in activated microglia and reactive astrocytes. As such, TSPO is a putative biomarker of neuroinflammation. We developed a second generation TSPO radioligand, [11C]PBR28, which is now used worldwide at several PET centers to explore neuroinflammation. Using this radioligand, we found elevated TSPO density in unmedicated patients with major depressive disorder (MDD) and in patients with Alzheimer’s disease (AD). Using a recently developed third-generation TSPO radioligand, [11C]ER176, we plan to explore neuroinflammation that may exist in HIV+ patients with cognitive impairment and in rare, genetically-associated forms of frontotemporal dementia (FTD).

Project 2: Neuroinflammation and COX

Building on our work with TSPO, and to make the connection to experimental medicine, we developed radioligands for cyclooxygenase-1 (COX-1) and COX-2, which are themselves targets of non-steroidal anti-inflammatory drugs (NSAIDs). These radioligands—[11C]PS13 for COX-1 and [11C]MC1 for COX-2—are potent and selective for each isoform and have shown promising results in monkeys and humans. We found that COX-1 is expressed constitutively (i.e., under healthy conditions) in several organs, including brain, spleen, kidney, and GI tract. The binding of the COX-1 radioligand was selective for its targeted isozyme, as it could be blocked by COX-1-selective inhibitors in both monkeys and humans, but not by COX-2-selective inhibitors. To evaluate [11C]MC1, we first had to upregulate COX-2 in monkey brain using intracerebral injection of the inflammogen lipopolysaccharide (LPS). Under baseline/healthy conditions, [11C]MC1 detected no COX-2 in brain. However, after LPS injection, [11C]MC1 clearly visualized areas of elevated COX-2 and showed appropriate subtype selectivity. Our interpretation was that [11C]MC1 lacked the sensitivity to measure the low baseline concentrations of COX-2, but could detect the enzyme after upregulation, which can be a 10- to 20-fold effect. To determine whether [11C]MC1 can detect COX-2 in human participants, we studied individuals with rheumatoid arthritis (RA), as COX-2 is upregulated in the affected joints. In the four participants studied to date, symptomatic joints had increased uptake of [11C]MC1, which was blocked by celecoxib. These preliminary results confirmed that [11C]MC1 is capable of imaging COX-2 in humans if COX-2 concentrations are elevated by peripheral inflammation. The ligands will next be used to explore the pathophysiological role of neuroinflammation in dementias and depression.

Project 3: Phosphodiesterase-4 (PDE4)

PDE4 metabolizes and thereby terminates the actions of cAMP. Rolipram is a reversible PDE4 inhibitor, and binding of [11C](R)-rolipram provides a measure of the activity of this enzyme in brain. Consistent with the ‘cAMP theory of depression’, we found that [11C](R)-rolipram binding is decreased in unmedicated patients with major depressive disorder (MDD) and increased (normalized) after two months of treatment with a selective serotonin reuptake inhibitor (SSRI). Rolipram was developed by Pfizer in the 1990s as a potential antidepressant and was shown to have some preliminary antidepressant effects, but studies were terminated because of nausea and vomiting. It was subsequently learned that PDE4 has four subtypes, and that rolipram inhibits all four. Pharmaceutical companies sought to develop a subtype-selective PDE4 inhibitor, hoping that it would have antidepressant efficacy but lack side effects. We successfully collaborated with Mark Gurney (Tetra Discovery Partners) to develop a radioligand selective for PDE4D and recently began first-in-human studies. Our initial goal is to assess target engagement with the therapeutic candidate and, if successful, proceed to clinical trials in MDD, as animal studies suggest that inhibition of PDE4D has both antidepressant and pro-cognitive effects.


The significance of this work can be assessed relative to its intrinsic scientific impact as well as its overall impact on the field of molecular imaging. With regard to intrinsic scientific impact, our research is widely respected as some of the most rigorous and valuable investigation into new areas of general importance to the field. As an example, imaging of TSPO with the prototypical radioligand [11C]PK11195 was flawed by poorly reproducible results due to a radioligand that had low specific signal. Our discovery and development of the second-generation radioligand [11C]PBR28, which has a much higher specific signal (Kobayashi et al., 2018), helped reinvigorate the imaging of neuroinflammation; the radioligand is now used at many PET centers throughout the world. Building on that work, our laboratory also developed [11C]-ER176, which is potentially even more useful to the field because of its even higher percentage-specific signal and its ability to measure TSPO in homozygous low-affinity binders (Ikawa et al., 2017).

Beyond its intrinsic scientific merit, this research has advanced the field of molecular imaging in several important ways.

  1. Developing radioligands. The crux of Drs. Innis and Pike’s work is to develop novel and truly useful radioligands with broad scientific utility. Towards this end, we have developed novel radioligands for more than 15 targets, and these are now used at centers throughout the world; these novel ligands are either measurably better than ligands previously in use or, often, are the first to successfully image a particular target. These targets include: TSPO, PDE4D, metabotropic glutamate receptor 1 (mGluR1), mGluR5, cannabinoid receptor type 1 (CB1), serotonin 1A receptor (5-HT1A), the nociceptin-orphanin peptide (NOP) receptor, OGlcNAcase (an enzyme involved in tau protein clearance from brain), NR2B, COX-1, and COX-2, among others.
  2. Sharing expertise and information. The Molecular Imaging Branch has provided guidance to numerous PET centers and makes critical information regarding the synthesis of radioligands publicly available. By the time of publication of the first human results, Drs. Innis and Pike post the complete Investigational New Drug application, which includes detailed information on synthesis and quality control; the animal toxicology data; the human protocol; the FDA review; our response to the review; and detailed instructions for synthesis and quality control (Chemistry, Manufacturing, and Controls).
  3. Senior advisor and leader. Dr. Innis is a highly regarded leader in the international field of brain PET imaging and is often consulted by researchers throughout the world for advice on radioligands, experimental and analytical methods, and regulatory issues. Perhaps his most important contributions in this area during the past four years have been establishing consensus on the format of content for PET data and spearheading a proposal to establish a PET archive. His efforts in this area continue to give significant structure to this growing field, vastly improving the sharing, reproducibility, and overall usefulness of results worldwide.
  4. Training. Dr. Innis has trained more than 60 graduate students and postdoctoral fellows. This talented crop of future leaders in the field have taken important positions in academia and industry.