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-HT_1A agonist, D2 agonist, NK₁, and 5-HT_y. 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.

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-HT_1A receptors in brain. J. Nucl. Med. 48: 1154 : 1161, 2007. (PDF File)

A.K. Brown, M. Fujita, Y. Fujimura, J.-S. Liow, M. Stabin, Y.H. Ryu, M. Imaizumi, J. Hong, V.W. Pike, and R.B. Innis. Radiation dosimetry and biodistribution in monkey and man of ¹¹C-PBR28, a PET radioligand to image inflammation. J. Nucl. Med. 48: 2072-2079, 2007. (PDF File)

S.S. Zoghbi, J.-S. Liow, F. Yasuno, J. Hong, E. Tuan, N. Lazarova, R.L. Gladding, V.W. Pike, and R.B. Innis. ¹¹C-Loperamide and its N-desmethyl radiometabolite are avid substrates for brain permeability-glycoprotein efflux. J. Nucl. Med., 49: 649-656, 2008. (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 D_2/3 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)