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Robert B. Innis, MD, PhD, Branch and Section Chief
OVERVIEW
This Section develops and uses PET (positron emission tomography) tracers as molecular probes of physiology and pathophysiology in animals and humans. In addition to traditional receptor targets, we use radiolabeled probes for in vivo imaging of intracellular signal transduction (e.g., cAMP phosphodiesterase), gene expression (e.g., dopamine transporters expressed on transplanted embryonic stem cells), and a mitochondrial protein that is a marker for inflammatory cells (activated microglia and macrophages). This Section includes multidisciplinary expertise in pharmacology, animal experimentation, clinical neuroscience, digital image analysis, and human evaluation of investigational radiopharmaceuticals.
Imaging is performed in primates and rodents to assess the utility of new probes and to explore models of human pathophysiology. For example, we imaged the serotonin transporter in adult monkeys with a history maternal deprivation to explore the role of serotonin in the abnormal behaviors of these animals (Ichise et al., 2006; see Recent Findings). In vivo imaging of rodents has allowed us to study valuable genetically-modified animals - e.g., mice that over express amyloid or those lacking an important drug efflux transporter (P-glycoprotein) at the blood brain barrier.
Approximately half of our PET scans are performed in humans, with several studies that are the "first-in-human" use of novel PET radioligands - e.g.,
a new probe for the metabotropic glutamate subtype 5 (mGluR5) receptor, the cannabinoid CB1 receptor, a probe for cellular inflammation, and a substrate for P-glycoprotein transporter at the blood-brain barrier. We have several on-going or soon-to-be-started studies including imaging of neuroinflammation in patients with multiple sclerosis, Alzheimer�s disease, and AIDS dementia; measurement of the cAMP system in patients with depression, before and after antidepressant treatment; and imaging the cannabinoid CB1 receptor in alcoholism during phases of withdrawal.
Contact Information
Robert B. Innis, MD, PhD
Chief, Molecular Imaging Branch, NIMH
Bldg. 31, Rm. B2B37
31 Center Drive MSC 2035
Bethesda, MD 20892-2035
Office Tel: 301-594-1368
Secretary Tel: 301-594-1089:
Elizabeth Alzona
FAX: 301-480-3610
Email: robert.innis@nih.gov
PEOPLE
Elizabeth Alzona |
Administrative Branch Manager, (301) 594-1089, alzonae@irp.nimh.nih.gov |
Kacey Anderson |
Postbaccalaureate IRTA, (301) 594-1370, akacey@mail.nih.gov |
Leah Dickstein |
Postbaccalaureate IRTA, (301) 435-5821, dicksteinl@mail.nih.gov |
Maria D. Ferraris Araneta |
C-RNP Nurse Practitioner, (301) 496-9423, ferrarism@mail.nih.gov |
Masahiro Fujita |
M.D., Ph.D., Staff Scientist, (301) 451-8898, fujitam@intra.nimh.nih.gov |
Robert Gladding |
CNMT, Research PET Technologist, (301) 594-1432, gladdingr@mail.nih.gov |
Jussi Hirvonen |
M.D., Ph.D.; Special Volunteer, (301) 435-1695, hirvonenj@mail.nih.gov |
Gerald Hodges |
Nurse Specialist, (301) 496-1342, hodgesg@mail.nih.gov |
Robert Innis |
M.D., Ph.D, Branch and Section Chief, Senior Investigator, (301) 594-1368, Robert.Innis@nih.gov |
Kimberly Jenko |
Contractor, (301) 443-3007, jenkok@mail.nih.gov |
Pavitra Kannan |
Postbaccalaureate IRTA, (301) 594-5721, kannanp@mail.nih.gov |
Nobuyo Kimura |
MD, PhD, Special Volunteer, kimuran@mail.nih.gov |
Yasuyuki Kimura |
MD, PhD, Visiting Fellow, (301) 594-6236, kimuray@mail.nih.gov |
William C. Kreisl |
MD, Clinical Fellow, (301) 451-8894, kreislw@mail.nih.gov |
Jeih-San Liow |
Ph.D., Research Physicist, (301) 451-8862, Liowj@intra.nimh.nih.gov |
Garth Terry |
Predoctoral Fellow, (301) 594-1371, gartht@mail.nih.gov |
Sami Zoghbi |
Ph.D., Senior Research Scientist, (301) 435-7911, zoghbis@intra.nimh.nih.gov |
ON GOING PROJECTS
1) cAMP Phosphodiesterase4 (PDE4) in Depression..
The proposed mechanism of action of antidepressant medications is to upregulate the cAMP signal cascade. Phopshodiesterase4 (PDE4) is an enzyme that metabolizes cAMP and may have a mechanistic role in antidepressant efficacy. For example, chronic antidepressant treatment of animals increases PDE, and an inhibitor of PDE4 (rolipram) has antidepressant effects both in animals and humans. We evaluated the PET radioligand [11C](R)-rolipram in rodents. This ligand provides a robust signal in brain that can be quantified with the gold standard method of compartmental modeling of in vivo brain activity compared to serial measurements of the radioligand in arterial plasma (Fujita et al., 2005; see Recent Findings). Using an IND (Investigational New Drug) application, we've recently studied the safety, kinetics, and test/retest reproducibility of [11C](R)-rolipram in healthy subjects, and the results are quite promising. In collaboration with
Dr. Wayne Drevets, we are now imaging patients with major depression, before and after antidepressant treatment.
2) In Vivo Imaging of Inflammation.
The "peripheral benzodiazepine receptor" (PBR) is a protein of uncertain function that is highly expressed on the mitochondria wall of inflammatory cells: activated microglia in the central nervous system (CNS) and macrophages in the periphery. The name PBR is a misnomer, since it's also located in the CNS and has nothing to do with the classical benzodiazepine (or "Valium®") receptor. Nevertheless, PBR may be a useful biomarker of cellular inflammation.
We've developed several new radioligands that label PBRs with high affinity and low levels of nonspecific uptake in the surrounding tissue. As a test of their utility, we found that one such ligand [11C]PBR28 can image inflammation surrounding an experimentally-induced stroke in rat brain (Imaizumi et al., 2007; see Representative Publications). We've also tested three of these compounds in monkeys, and two have excellent kinetic properties with high ratios of specific to nonspecific uptake in brain. We recently completed studies with [11C]PBR28 in healthy human subjects, and the results to date are quite promising. (Fujita et al., 2008; see Representative Publications).
An imaging biomarker inflammation has many potentially useful applications, both in brain and the periphery. We are now using this PET radioligand in patients with multiple sclerosis, AIDS dementia, neurocysticercosis, Alzheimer’s disease, and atherosclerosis.
3) Imaging the Cannabinoid CB1 Receptor.
The cannabinoid CB1 receptor mediates the effects of marijuana and is one of the most abundant receptors in brain. The endocannabinoid neurotransmitter system as a whole is an active area for therapeutic drug development. For example, the FDA is currently reviewing the use of a CB1 antagonist in weight reduction, and this agent (rimonabant) may also be useful in cessation from smoking and drinking alcohol.
Most ligands for the CB1 receptor are highly lipophilic (i.e., fat soluble). Since fat composes about 70% of the dry weight of brain, these lipophilic ligands have high levels of nonspecific binding that overwhelm the smaller amounts of specific radioligand binding to CB1 receptors. We have developed a few PET radioligands for the CB1 receptor that show excellent imaging in nonhuman primates. We are now completing the evaluation in healthy human subjects for two different radioligands. One looks particularly promising, and we expect to begin studies in patients with alcoholism before the end of 2007.
4) Development of Novel Radioligands.
In close collaboration with Victor Pike's laboratory in the Molecular Imaging Branch, we are developing many new PET radioligands for protein targets in the brain. Our on-going projects include probes for amyloid, peripheral benzodiazepine receptor (inflammation), cAMP phospodiesterase4, P-glycoprotein efflux transporter, norepinephrine transporter, and receptors for mGluR5, mGluR1, 5-HT1A agonist, D2 agonist, NK1, and 5-HTy. Some of these projects are in collaboration with pharmaceutical companies, which provide significant expertise in the pharmacology of the target as well as extensive capacity for in vitro screening and medicinal chemistry.
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REPRESENTATIVE PUBLICATIONS
M. Ichise, D.C. Vines, T. Gura, G.M. Anderson, S.J. Suomi, J.D. Higley, R.B. Innis.
Effects of early life stress on [11C]DASB PET imaging of serotonin transporters in adolescent peer- and mother-reared rhesus monkeys. J. Neurosci. 26: 4638-4643, 2006. (PDF File)
M. Imaizumi, H.-J. Kim, S.S. Zoghbi, E. Briard, J. Hong, J.L. Musachio, J.M. Hallenbeck, C. Ruetzler, D-M. Chuang, V.W. Pike, R.B. Innis, and M. Fujita.
PET imaging with [11C]PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat. Neurosci. Lett.,
411: 200-205, 2007. (PDF File)
R.B. Innis and R.E. Carson with numerous supporting authors.
Consensus nomenclature for in vivo imaging of reversibly-binding radioligands. J. Cereb. Blood Flow Metab.,
27: 1533-1539, 2007. (PDF File)
M. Fujita, M. Imaizumi, S.S. Zoghbi, Y. Fujimura, A.G. Farris, T. Suhara, J. Hong, V.W. Pike, and R.B. Innis
Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. NeuroImage, 40: 43-52, 2008.
(PDF File)
Y.H. Ryu, J.-S. Liow, S.S. Zoghbi, M. Fujita, J. Collins, D. Tipre, J. Sangare, J. Hong, V.W. Pike, and R.B. Innis.
Disulfiram inhibits defluorination of [18F]FCWAY, reduces bone radioactivity, and enhances visualization of radioligand binding to 5-HT1A receptors in brain. J. Nucl. Med. 48: 1154 : 1161, 2007. (PDF File)
G. Terry, J.-S. Liow, E. Chernet, S.S. Zoghbi, L. Phebus, C.C. Felder, J. Tauscher, J.M. Schaus, V.W. Pike, C. Halldin, and R.B. Innis.
Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents. NeuroImage, 41: 690-698, 2008. (PDF File)
N. Seneca, S.S. Zoghbi, M. Skinbjerg, J.-S. Liow. J. Hong, D.R. Sibley, V.W. Pike, C. Halldin, and R.B. Innis.
Occupancy of dopamine D2/3 receptors in rat brain by endogenous dopamine measured with the agonist positron emission tomography radioligand [11C]MNPA. Synapse. 62: 756-763, 2008. (PDF File)
A.K. Brown, Y. Kimura, S.S. Zoghbi, F.G. Siméon, W.C. Kreisl, A. Taku, M. Fujita, V.W. Pike, and R.B. Innis.
Metabotropic glutamate subtype 5 (mGluR5) receptors quantified in human brain with a novel radioligand for positron emission tomography. J. Nucl. Med., 49: 2042-2048, 2008. (PDF File)
J.-S. Liow, W. Kreisl, S.S. Zoghbi, N. Lazarova, N. Seneca, R.L. Gladding, A. Taku, P. Herscovitch, V.W. Pike, and R.B. Innis.
P-glycoprotein function at the blood-brain barrier imaged using 11C-N-desmethyl-loperamide in monkeys. J. Nucl. Med., 50: 108-115, 2009. (PDF File)
Y. Fujimura, F. Yasuno, A. Farris, J.-S. Liow, M. Geraci, W. Drevets, D.S. Pine, S. Ghose, A. Lerner, R. Hargreaves, H.D. Burns, C. Morse, V.W. Pike, and R.B. Innis.
Decreased neurokinin1 (substance P) receptor binding in patients with panic disorder: positron emission tomographic study with [18F]SPA-RQ. Biol. Psychiatry, In Press. (PDF File)
N. Seneca, S. S. Zoghbi, J.-S. Liow, W. Kreisl, P. Herscovitch, K. Jenko, R.L. Gladding, A. Taku, V.W. Pike, and R.B. Innis.
. Human brain imaging and radiation dosimetry of 11C-N-desmethyl-loperamide, a positron emission tomographic radiotracer to measure the function of P-glycoprotein. J. Nucl. Med., 50: 807-813, 2009. (PDF File)
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