Examples of progress made during the prior year are summarized below. 1) We demonstrated that, in human brain, binding of 11C(R)-rolipram to phosphodiesterase 4 (PDE4) could be quantified using kinetic modeling and an arterial input function. Furthermore, image input function from carotid arteries was found to provide an equally accurate and reproducible method of quantifying PDE4 (Zanotti Fregonara et al, 2011). 11C(R)-rolipram measures the density of phosphodiesterase 4 (PDE4) in brain;PDE4, in turn, is an enzyme that metabolizes cyclic adenosine monophospate (cAMP).
The aims of this study were to perform kinetic modeling of 11C(R)-rolipram in healthy humans using an arterial input function and to replace this arterial input in humans with an image-derived input function. Twelve humans had two injections of 11C(R)-rolipram. An image-derived input function was obtained from the carotid arteries and four blood samples. The samples were used for partial volume correction and for estimating the parent concentration using high-performance liquid chromatography (HPLC) analysis. An unconstrained two-compartment model and Logan analysis measured distribution volume (VT), with good identifiability but with moderately high retest variability (15%). Similar results were obtained using the image input (ratio image/arterial VT=1.000.06). Taken together, the data demonstrate that binding of 11C(R)-rolipram to PDE4 can be quantified in human brain using kinetic modeling and an arterial input function, and that image input function from carotid arteries provides an equally accurate and reproducible method of quantifying PDE4. 2) We conducted a study that was the first to demonstrate that cortical cannabinoid CB1 (cannabinoid receptor type 1) downregulation may be a neuroadaptation that promotes cannabis dependence in human brain (Hirvonen et al 2011). Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies had shown reversible downregulation of brain cannabinoid CB1 receptors after chronic exposure to cannabis. However, whether downregulation occured in humans who chronically smoked cannabis was unknown. Using PET imaging, we found reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoked cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After approximately four weeks of continuously monitored abstinence from cannabis on a secure research unit, CB1 receptor density returned to normal levels. This study was the first direct demonstration of cortical cannabinoid CB1 receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain. 3) We used the novel radioligand 11C-PBR28 to measure Translocator protein 18 kDa (TSPO), a marker of inflammation, in the living human brain of subjects with temporal lobe epilepsy. We found increased uptake of radioactivity after injection of 11C-PBR28 ipsilateral to seizure focus in patients with temporal lobe epilepsy, consistent with increased expression of TSPO (Hirvonen et al, in press). Animal studies and clinical observations suggest that epilepsy is associated with inflammation. TSPO, a marker of inflammation, is increased in vitro in surgical samples from patients with temporal lobe epilepsy. TSPO can be measured in the living human brain with PET and the novel radioligand 11C-PBR28. In this study, we sought to determine if in vivo expression of TSPO is increased ipsilateral to the seizure focus in patients with temporal lobe epilepsy. Sixteen patients with unilateral temporal lobe epilepsy and 30 healthy subjects were studied with 11C-PBR28 PET and MRI. Uptake of radioactivity after injection of 11C-PBR28 was measured from regions of interest drawn bilaterally onto MR images. Brain uptake from ipsilateral and contralateral hemispheres was compared using a paired samples t-test. We found that brain uptake was higher ipsilateral to the seizure focus in the hippocampus, parahippocampal gyrus, amygdala, fusiform gyrus, and choroid plexus, but not in other brain regions. This asymmetry was more pronounced in patients with hippocampal sclerosis than in those without. We found increased uptake of radioactivity after injection of 11C-PBR28 ipsilateral to seizure focus in patients with temporal lobe epilepsy, consistent with increased expression of TSPO. We plan to confirm this initial observation in larger samples, establish whether other brain regions are involved, and measure absolute binding values using fully quantitative analysis. However, it appears that TSPO imaging may be key to the pathophysiology and treatment of temporal lobe epilepsy.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2011
Total Cost
$2,981,746
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
Zip Code
Kreisl, William C; Lyoo, Chul Hyoung; Liow, Jeih-San et al. (2017) Distinct patterns of increased translocator protein in posterior cortical atrophy and amnestic Alzheimer's disease. Neurobiol Aging 51:132-140
Kreisl, William C; Lawrence, Robin; Page, Emily et al. (2017) 11C-PBR28 PET detects translocator protein in a patient with astrocytoma and Alzheimer disease. Neurology 88:1001-1004
Ikawa, Masamichi; Lohith, Talakad G; Shrestha, Stal et al. (2017) 11C-ER176, a Radioligand for 18-kDa Translocator Protein, Has Adequate Sensitivity to Robustly Image All Three Affinity Genotypes in Human Brain. J Nucl Med 58:320-325
Kobayashi, Masato; Jiang, Teresa; Telu, Sanjay et al. (2017) (11)C-DPA-713 has much greater specific binding to translocator protein 18?kDa (TSPO) in human brain than (11)C-( R)-PK11195. J Cereb Blood Flow Metab :271678X17699223
Brouwer, Chad; Jenko, Kimberly J; Zoghbi, Sami S et al. (2016) Translocator protein ligands based on N-methyl-(quinolin-4-yl)oxypropanamides with properties suitable for PET radioligand development. Eur J Med Chem 124:677-688
Veronese, Mattia; Zanotti-Fregonara, Paolo; Rizzo, Gaia et al. (2016) Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot. Neuroimage 130:1-12
Kreisl, William C; Lyoo, Chul Hyoung; Liow, Jeih-San et al. (2016) (11)C-PBR28 binding to translocator protein increases with progression of Alzheimer's disease. Neurobiol Aging 44:53-61
Liow, Jeih-San; Zoghbi, Sami S; Hu, Shuo et al. (2016) (18)F-FCWAY, a serotonin 1A receptor radioligand, is a substrate for efflux transport at the human blood-brain barrier. Neuroimage 138:134-140
Zanotti-Fregonara, Paolo; Xu, Rong; Zoghbi, Sami S et al. (2016) The PET Radioligand 18F-FIMX Images and Quantifies Metabotropic Glutamate Receptor 1 in Proportion to the Regional Density of Its Gene Transcript in Human Brain. J Nucl Med 57:242-7
Lyoo, Chul Hyoung; Ikawa, Masamichi; Liow, Jeih-San et al. (2015) Cerebellum Can Serve As a Pseudo-Reference Region in Alzheimer Disease to Detect Neuroinflammation Measured with PET Radioligand Binding to Translocator Protein. J Nucl Med 56:701-6

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