400 results on '"Innis RB"'
Search Results
2. Evaluation of Novel N1-Methyl-2-phenylindol-3-ylglyoxylamides as a New Chemotype 2 of 18 kDa Translocator Protein-Selective Ligand Suitable for the Development 3 of Positron Emission Tomography Radioligands
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Pike, Vw, Taliani, Sabrina, Lohith, Tg, Owen, R, Pugliesi, I, DA POZZO, Eleonora, Hong, J, Zoghbi, Ss, Gunn, R, Parker, Ca, Rabiner, Ea, Fujita, M, Innis, Rb, Martini, Claudia, and DA SETTIMO PASSETTI, Federico
- Published
- 2011
3. Glutamate-dopamine interaction in awake rats and monkeys assessed by PET and dopamine D2/3 receptor agonist radiotracer [11C]MNPA
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Tokunaga, Masaki, Seneca, Nicholas, Maeda, Jun, Shin, Ryong-Moon, Ki, Hin, Okauchi, Takashi, Maruyama, Masahiro, Innis, Rb, Halldin, Christer, Suzuki, Kazutoshi, Higuchi, Makoto, and Suhara, Tetsuya
- Abstract
MEUROSCIENCE 2007
- Published
- 2007
4. Quantification of central serotonin transporter binding potential and relative tracer delivery by using multilinear reference tissue models for human [11C]DASB PET studies
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Ichise, M, Loiw, Js, Lu, Jq, Takano, Akihiro, Modell, K, Toyama, Hinako, Suhara, Tetsuya, Innis, Rb, and Carson, Re
- Abstract
50th Annual meeting of the Society of Nuclear Medicine
- Published
- 2003
5. Contribution of scatter and attenuation compensation to SPECT images of nonuniformly distributed brain activities
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Kim KM, Varrone A, Watabe H, Shidahara M, Fujita M, Innis RB, and Iida H.
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SPECT ,Tomografia Emissiva ,Analisi Quantitativa - Abstract
Correction of scatter and attenuation is essential for quantitative SPECT. In this work, we evaluated the accuracy gained from a method of transmission-dependent convolution subtraction (TDCS) in the quantitation of activity that is highly concentrated in the striatum (STR). METHODS: SPECT data were acquired from an (123)I-containing phantom with a constant activity in the STR but differing background (BKG) activities, so as to simulate various STR/BKG ratios (19.7:1, 9.7:1, 4.8:1, 1.9:1, and 1:1). In a study of healthy humans (n = 6), a transmission scan followed by an emission scan was performed 24 h after injection of (123)I-2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ((123)I-beta-CIT). All SPECT data was reconstructed with ordered-subset expectation maximization. TDCS was applied for scatter correction. Values of activity in the STR and occipital lobe (for BKG) were used to calculate binding potential V(3)" (= [STR - BKG]/BKG). The effect of SPECT collimator dependency on scatter correction was also evaluated for 6 collimators from 3 different SPECT cameras in the phantom experiment. RESULTS: Scatter correction in the phantom experiment increased the measured values of STR activity (36.2%), resulting in a substantial increase in V(3)" (66.1%). Scatter and attenuation corrections with recovery correction showed an overall bias of -7.3% for the STR, -4.0% for BKG activity, and -7.8% for V(3)". TDCS corrections of phantom activities were relatively uniform for the 6 different collimators, with variabilities of
- Published
- 2003
6. PET Reveals Inflammation around Calcified Taenia solium Granulomas with Perilesional Edema
- Author
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Preux, P-M, Fujita, M, Mahanty, S, Zoghbi, SS, Araneta, MDF, Hong, J, Pike, VW, Innis, RB, Nash, TE, Preux, P-M, Fujita, M, Mahanty, S, Zoghbi, SS, Araneta, MDF, Hong, J, Pike, VW, Innis, RB, and Nash, TE
- Abstract
OBJECTIVE: Neurocysticercosis, an infection with the larval form of the tapeworm, Taeniasolium, is the cause of 29% of epilepsy in endemic regions. Epilepsy in this population is mostly associated with calcified granulomas; at the time of seizure recurrence 50% of those with calcifications demonstrate transient surrounding perilesional edema. Whether edema is consequence of the seizure, or a result of host inflammation directed against parasite antigens or other processes is unknown. To investigate whether perilesional edema is due to inflammation, we imaged a marker of neuroinflammation, translocater protein (TSPO), using positron emission tomography (PET) and the selective ligand (11)C-PBR28. METHODS: In nine patients with perilesional edema, degenerating cyst or both, PET findings were compared to the corresponding magnetic resonance images. Degenerating cysts were also studied because unlike perilesional edema, degenerating cysts are known to have inflammation. In three of the nine patients, changes in (11)C-PBR28 binding were also studied over time. (11)C-PBR28 binding was compared to the contralateral un-affected region. RESULTS: (11)C-PBR28 binding increased by a mean of 13% in perilesional edema or degenerating cysts (P = 0.0005, n = 13 in nine patients). Among these 13 lesions, perilesional edema (n=10) showed a slightly smaller increase of 10% compared to the contralateral side (P = 0.005) than the three degenerating cysts. In five lesions with perilesional edema in which repeated measurements of (11)C-PBR28 binding were done, increased binding lasted for 2-9 months. CONCLUSIONS: Increased TSPO in perilesional edema indicates an inflammatory etiology. The long duration of increased TSPO binding after resolution of the original perilesional edema and the pattern of periodic episodes is consistent with intermittent exacerbation from a continued baseline presence of low level inflammation. Novel anti-inflammatory measures may be useful in the prevention or tr
- Published
- 2013
7. Images in neuroscience. SPECT imaging of synaptic dopamine
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Laruelle M and Innis Rb
- Subjects
Dextroamphetamine ,Pyrrolidines ,business.industry ,Dopamine ,Brain ,Contrast Media ,Receptors, Dopamine ,Iodine Radioisotopes ,Psychiatry and Mental health ,Text mining ,Spect imaging ,Benzamides ,Synapses ,medicine ,Humans ,Radionuclide Imaging ,business ,Neuroscience ,medicine.drug - Published
- 1996
8. PET [11C]DASB imaging of serotonin transporters in patients with alcoholism.
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Brown AK, George DT, Fujita M, Liow J, Ichise M, Hibbeln J, Ghose S, Sangare J, Hommer D, and Innis RB
- Abstract
Objective: Alcoholism and aggression have each been associated with neurochemical measurements suggestive of decreased serotonin synaptic transmission. We measured densities of the serotonin transporter (SERT) in a moderate-sized sample of alcoholic patients who were assessed for aggressive characteristics. Methods: Thirty alcoholic inpatients and 18 healthy controls received a PET scan with [
11 C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl )-benzonitrile. The alcoholic inpatients were classified as aggressive or nonaggressive based on a comparison between the top third and bottom third scores on the Buss-Durkee Hostility Index. Results: Using a pixel-wise comparison, no brain region showed significant alterations in SERT binding among the 3 groups of subjects (aggressive alcoholic subjects, nonaggressive alcoholic subjects, and healthy controls) or between the combined alcoholic group and healthy controls. None of the clinical measures (including measures of aggression) correlated with SERT binding in the alcoholic subjects. Conclusion: Contrary to prior imaging reports using the nonselective ligand [123 I] [beta]-CIT, we found no significant alterations of SERT density in alcoholic patients. [ABSTRACT FROM AUTHOR]- Published
- 2007
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9. Widespread decrease of nicotinic acetylcholine receptors in Parkinson's disease.
- Author
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Fujita M, Ichise M, Zoghbi SS, Liow JS, Ghose S, Vines DC, Sangare J, Lu JQ, Cropley VL, Iida H, Kim KM, Cohen RM, Bara-Jimenez W, Ravina B, and Innis RB
- Published
- 2006
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10. Evaluation of 2 scatter correction methods using a striatal phantom for quantitative brain SPECT.
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Vines DC, Ichise M, Liow J, Toyama H, and Innis RB
- Published
- 2003
11. Autoradiographic localization of cholecystokinin receptors in rodent brain
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Zarbin, MA, primary, Innis, RB, additional, Wamsley, JK, additional, Snyder, SH, additional, and Kuhar, MJ, additional
- Published
- 1983
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12. Binding of a tritiated inverse agonist to cannabinoid CB1 receptors is increased in patients with schizophrenia.
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Jenko KJ, Hirvonen J, Henter ID, Anderson KB, Zoghbi SS, Hyde TM, Deep-Soboslay A, Innis RB, Kleinman JE, Jenko, Kimberly J, Hirvonen, Jussi, Henter, Ioline D, Anderson, Kacey B, Zoghbi, Sami S, Hyde, Thomas M, Deep-Soboslay, Amy, Innis, Robert B, and Kleinman, Joel E
- Abstract
This study sought to determine whether cannabinoid-1 (CB(1)) receptor binding was altered in the postmortem dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia (schizophrenia; n=47) compared to controls (n=43). The CB(1) receptor inverse agonist radioligand [(3)H]MePPEP was used to measure specific binding to CB(1) receptors. The specific binding of [(3)H]MePPEP to CB(1) receptors was 20% higher in patients with schizophrenia than in controls. Power analyses suggested that 53 subjects per group would be needed to detect a similar difference in vivo with positron emission tomography (PET) and the structurally related inverse agonist radioligand [(18)F]FMPEP-d(2) (80% statistical power, p<0.05). [ABSTRACT FROM AUTHOR]
- Published
- 2012
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13. PET imaging in rat brain shows opposite effects of acute and chronic alcohol exposure on phosphodiesterase-4B, an indirect biomarker of cAMP activity.
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Tang S, Kim SW, Olsen-Dufour A, Pearson T, Freaney M, Singley E, Jenkins M, Burkard NJ, Wozniak A, Parcon P, Wu S, Morse CL, Jana S, Liow JS, Zoghbi SS, Vendruscolo JCM, Vendruscolo LF, Pike VW, Koob GF, Volkow ND, and Innis RB
- Abstract
The cyclic adenosine monophosphate (cAMP) cascade is thought to play an important role in regulating alcohol-dependent behaviors, with potentially opposite effects following acute versus chronic administration. Phosphodiesterase 4 (PDE4) is the primary brain enzyme that metabolizes cAMP, thereby terminating its signal. Radioligand binding to PDE4 serves as an indirect biomarker of cAMP activity, as cAMP-protein kinase A (PKA)-mediated phosphorylation of PDE4 increases its affinity for radioligand binding ~10-fold. Of the four PDE4 subtypes, PDE4B polymorphisms are known to be strongly associated with alcohol and substance use disorders. This study imaged rats with the PDE4B-preferring positron emission tomography (PET) radioligand [
18 F]PF-06445974 following acute and chronic ethanol administration, aiming to explore the potential of PDE4B PET imaging for future human studies. Compared to the control group treated with saline, acute alcohol administration (i.p. ethanol 0.5 g/kg) significantly increased whole brain uptake of [18 F]PF-06445974 as early as 30 minutes post-exposure. This effect persisted at 2 hours, peaked at 4 hours, and diminished at 6 hours and 24 hours post-exposure. In contrast, in a rat model of alcohol dependence, [18 F]PF-06445974 brain uptake was significantly reduced at 5 hours post-exposure and was normalized by 3 days. This reduction may reflect long-term adaptation to repeated alcohol-induced activation of cAMP signaling with chronic exposure. Taken together, the results suggest that PET imaging of PDE4B in individuals with alcohol use disorder (AUD) should be considered in conjunction with ongoing trials of PDE4 inhibitors to treat alcohol withdrawal and reduce alcohol consumption., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2024
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14. Evaluation of [ 18 F]fluoroestradiol and ChRERα as a gene expression PET reporter system in rhesus monkey brain.
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Li B, Wadhwa P, Lerchner W, Zanotti-Fregonara P, Liow JS, Yan X, Zoghbi SS, Nerella SG, Telu S, Morse CL, Solis O, Gomez JL, Holt DP, Dannals RF, Cummins AC, Innis RB, Pike VW, Richmond BJ, Michaelides M, and Eldridge MAG
- Subjects
- Animals, Fluorine Radioisotopes, Receptors, Estrogen metabolism, Receptors, Estrogen genetics, Genetic Vectors genetics, Genetic Vectors administration & dosage, Gene Expression, RNA, Small Interfering genetics, Lentivirus genetics, Humans, Macaca mulatta, Positron-Emission Tomography methods, Estradiol analogs & derivatives, Estradiol pharmacology, Brain metabolism, Brain diagnostic imaging, Genes, Reporter
- Abstract
Positron emission tomography (PET) reporter systems are a valuable means of estimating the level of expression of a transgene in vivo. For example, the safety and efficacy of gene therapy approaches for the treatment of neurological and neuropsychiatric disorders could be enhanced via the monitoring of exogenous gene expression levels in the brain. The present study evaluated the ability of a newly developed PET reporter system [
18 F]fluoroestradiol ([18 F]FES) and the estrogen receptor-based PET reporter ChRERα, to monitor expression levels of a small hairpin RNA (shRNA) designed to suppress choline acetyltransferase (ChAT) expression in rhesus monkey brain. The ChRERα gene and shRNA were expressed from the same transcript via lentivirus injected into monkey striatum. In two monkeys that received injections of viral vector, [18 F]FES binding increased by 70% and 86% at the target sites compared with pre-injection, demonstrating that ChRERα expression could be visualized in vivo with PET imaging. Post-mortem immunohistochemistry confirmed that ChAT expression was significantly suppressed in regions in which [18 F]FES uptake was increased. The consistency between PET imaging and immunohistochemical results suggests that [18 F]FES and ChRERα can serve as a PET reporter system in rhesus monkey brain for in vivo evaluation of the expression of potential therapeutic agents, such as shRNAs., Competing Interests: Declaration of interests M.M. has received research funding from AstraZeneca, Kriya (Redpin) Therapeutics, Dompé farmaceutici, and Attune Neurosciences, and is named as an inventor on a patent describing novel DREADD ligands (WO2019/157083) and a U.S. provisional patent application describing novel fluorinated mu opioid receptor agonists (63/452,879)., (Published by Elsevier Inc.)- Published
- 2024
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15. Robust Quantification of Phosphodiesterase-4D in Monkey Brain with PET and 11 C-Labeled Radioligands That Avoid Radiometabolite Contamination.
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Jiang M, Tang S, Jenkins MD, Lee AC, Kenou B, Knoer C, Montero Santamaria J, Wu S, Liow JS, Zoghbi SS, Zanotti-Fregonara P, Innis RB, Telu S, and Pike VW
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- Animals, Ligands, Radiopharmaceuticals pharmacokinetics, Radiopharmaceuticals chemistry, Male, Isotope Labeling, Phosphodiesterase 4 Inhibitors chemistry, Humans, Positron-Emission Tomography, Carbon Radioisotopes, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Brain diagnostic imaging, Brain metabolism, Macaca mulatta
- Abstract
Phosphodiesterase-4D (PDE4D) has emerged as a significant target for treating neuropsychiatric disorders, but no PET radioligand currently exists for robustly quantifying human brain PDE4D to assist biomedical research and drug discovery. A prior candidate PDE4D PET radioligand, namely [
11 C]T1650, failed in humans because of poor time stability of brain PDE4D-specific signal (indexed by total volume of distribution), likely due to radiometabolites accumulating in brain. Its nitro group was considered to be a source of the brain radiometabolites. Methods: We selected 5 high-affinity and selective PDE4D inhibitors, absent of a nitro group, from our prior structure-activity relationship study for evaluation as PET radioligands. Results: All 5 radioligands were labeled with11 C (half-time, 20.4 min) in useful yields and with high molar activity. All displayed sizable PDE4D-specific signals in rhesus monkey brain. Notably, [11 C]JMJ-81 and [11 C]JMJ-129 exhibited excellent time stability of signal (total volume of distribution). Furthermore, as an example, [11 C]JMJ-81 was found to be free of radiometabolites in ex vivo monkey brain, affirming that this radioligand can provide robust quantification of brain PDE4D with PET. Conclusion: Given their high similarity in structures and metabolic profiles, both [11 C]JMJ-81 and [11 C]JMJ-129 warrant further evaluation in human subjects. [11 C]JMJ-129 shows a higher PDE4D specific-to-nonspecific binding ratio and will be the first to be evaluated., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2024
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16. The past, present, and future of the brain imaging data structure (BIDS).
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Poldrack RA, Markiewicz CJ, Appelhoff S, Ashar YK, Auer T, Baillet S, Bansal S, Beltrachini L, Benar CG, Bertazzoli G, Bhogawar S, Blair RW, Bortoletto M, Boudreau M, Brooks TL, Calhoun VD, Castelli FM, Clement P, Cohen AL, Cohen-Adad J, D'Ambrosio S, de Hollander G, de la Iglesia-Vayá M, de la Vega A, Delorme A, Devinsky O, Draschkow D, Duff EP, DuPre E, Earl E, Esteban O, Feingold FW, Flandin G, Galassi A, Gallitto G, Ganz M, Gau R, Gholam J, Ghosh SS, Giacomel A, Gillman AG, Gleeson P, Gramfort A, Guay S, Guidali G, Halchenko YO, Handwerker DA, Hardcastle N, Herholz P, Hermes D, Honey CJ, Innis RB, Ioanas HI, Jahn A, Karakuzu A, Keator DB, Kiar G, Kincses B, Laird AR, Lau JC, Lazari A, Legarreta JH, Li A, Li X, Love BC, Lu H, Marcantoni E, Maumet C, Mazzamuto G, Meisler SL, Mikkelsen M, Mutsaerts H, Nichols TE, Nikolaidis A, Nilsonne G, Niso G, Norgaard M, Okell TW, Oostenveld R, Ort E, Park PJ, Pawlik M, Pernet CR, Pestilli F, Petr J, Phillips C, Poline JB, Pollonini L, Raamana PR, Ritter P, Rizzo G, Robbins KA, Rockhill AP, Rogers C, Rokem A, Rorden C, Routier A, Saborit-Torres JM, Salo T, Schirner M, Smith RE, Spisak T, Sprenger J, Swann NC, Szinte M, Takerkart S, Thirion B, Thomas AG, Torabian S, Varoquaux G, Voytek B, Welzel J, Wilson M, Yarkoni T, and Gorgolewski KJ
- Abstract
The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS., Competing Interests: Gaia Rizzo is an employee of Invicro. No other authors have competing interests to declare., (© 2024 Massachusetts Institute of Technology. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)
- Published
- 2024
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17. Synthesis and preclinical evaluation of [ 11 C]uPSEM792 for PSAM 4 -GlyR based chemogenetics.
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Nerella SG, Telu S, Liow JS, Jenkins MD, Zoghbi SS, Gomez JL, Michaelides M, Eldridge MAG, Richmond BJ, Innis RB, and Pike VW
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- Tomography, X-Ray Computed, Biological Transport, Signal Transduction, Receptors, Glycine genetics, Serotonin
- Abstract
Chemogenetic tools are designed to control neuronal signaling. These tools have the potential to contribute to the understanding of neuropsychiatric disorders and to the development of new treatments. One such chemogenetic technology comprises modified Pharmacologically Selective Actuator Modules (PSAMs) paired with Pharmacologically Selective Effector Molecules (PSEMs). PSAMs are receptors with ligand-binding domains that have been modified to interact only with a specific small-molecule agonist, designated a PSEM. PSAM
4 is a triple mutant PSAM derived from the α7 nicotinic receptor (α7L131G,Q139L,Y217F ). Although having no constitutive activity as a ligand-gated ion channel, PSAM4 has been coupled to the serotonin 5-HT3 receptor (5-HT3 R) and to the glycine receptor (GlyR). Treatment with the partner PSEM to activate PSAM4 -5-HT3 or PSAM4 -GlyR, causes neuronal activation or silencing, respectively. A suitably designed radioligand may enable selective visualization of the expression and location of PSAMs with positron emission tomography (PET). Here, we evaluated uPSEM792, an ultrapotent PSEM for PSAM4 -GlyR, as a possible lead for PET radioligand development. We labeled uPSEM792 with the positron-emitter, carbon-11 (t1/2 = 20.4 min), in high radiochemical yield by treating a protected precursor with [11 C]iodomethane followed by base deprotection. PET experiments with [11 C]uPSEM792 in rodents and in a monkey transduced with PSAM4 -GlyR showed low peak radioactivity uptake in brain. This low uptake was probably due to high polarity of the radioligand, as evidenced by physicochemical measurements, and to the vulnerability of the radioligand to efflux transport at the blood-brain barrier. These findings can inform the design of a more effective PSAM4 based PET radioligand, based on the uPSEM792 chemotype., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2024
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18. PET2BIDS: a library for converting Positron Emission Tomography data to BIDS.
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Galassi A, Norgaard M, Thomas AG, Gonzalez-Escamilla G, Svarer C, Rorden C, Matheson GJ, Knudsen GM, Innis RB, Ganz M, Eierud C, Bilgel M, and Pernet C
- Published
- 2024
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19. PET reporter systems for the brain.
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Nerella SG, Michaelides M, Minamimoto T, Innis RB, Pike VW, and Eldridge MAG
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- Humans, Genes, Reporter, Central Nervous System, Positron-Emission Tomography methods, Brain diagnostic imaging, Brain metabolism
- Abstract
Positron emission tomography (PET) can be used as a noninvasive method to longitudinally monitor and quantify the expression of proteins in the brain in vivo. It can be used to monitor changes in biomarkers of mental health disorders, and to assess therapeutic interventions such as stem cell and molecular genetic therapies. The utility of PET monitoring depends on the availability of a radiotracer with good central nervous system (CNS) penetration and high selectivity for the target protein. This review evaluates existing methods for the visualization of reporter proteins and/or protein function using PET imaging, focusing on engineered systems, and discusses possible approaches for future success in the development of high-sensitivity and high-specificity PET reporter systems for the brain., Competing Interests: Declaration of interests M.M. has received research funding from AstraZeneca, Redpin Therapeutics, Dompé Farmaceutici, and Attune Neurosciences, and is named as an inventor on a patent describing novel DREADD ligands (WO2019/157083). T.M. is named as an inventor on a patent for the use of DCZ as a PET reporter probe (WO2019/245047). The other coauthors declare no conflicts of interest., (Published by Elsevier Ltd.)
- Published
- 2023
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20. In vivo evaluation of a novel 18 F-labeled PET radioligand for translocator protein 18 kDa (TSPO) in monkey brain.
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Yan X, Siméon FG, Liow JS, Morse CL, Montero Santamaria JA, Jenkins M, Manly LS, Van Buskirk M, Zoghbi SS, Pike VW, Innis RB, and Zanotti-Fregonara P
- Subjects
- Humans, Mice, Animals, Positron-Emission Tomography methods, Carrier Proteins metabolism, Protein Binding, Radiopharmaceuticals metabolism, Receptors, GABA metabolism, Brain diagnostic imaging, Brain metabolism
- Abstract
Purpose: [
18 F]SF51 was previously found to have high binding affinity and selectivity for 18 kDa translocator protein (TSPO) in mouse brain. This study sought to assess the ability of [18 F]SF51 to quantify TSPO in rhesus monkey brain., Methods: Positron emission tomography (PET) imaging was performed in monkey brain (n = 3) at baseline and after pre-blockade with the TSPO ligands PK11195 and PBR28. TSPO binding was calculated as total distribution volume corrected for free parent fraction in plasma (VT /fP ) using a two-tissue compartment model. Receptor occupancy and nondisplaceable uptake were determined via Lassen plot. Binding potential (BPND ) was calculated as the ratio of specific binding to nondisplaceable uptake. Time stability of VT was used as an indirect probe to detect radiometabolite accumulation in the brain. In vivo and ex vivo experiments were performed in mice to determine the distribution of the radioligand., Results: After [18 F]SF51 injection, the concentration of brain radioactivity peaked at 2.0 standardized uptake value (SUV) at ~ 10 min and declined to 30% of the peak at 180 min. VT /fP at baseline was generally high (203 ± 15 mL· cm-3 ) and decreased by ~ 90% after blockade with PK11195. BPND of the whole brain was 7.6 ± 4.3. VT values reached levels similar to terminal 180-min values by 100 min and remained relatively stable thereafter with excellent identifiability (standard errors < 5%), suggesting that no significant radiometabolites accumulated in the brain. Ex vivo experiments in mouse brain showed that 96% of radioactivity was parent. No significant uptake was observed in the skull, suggesting a lack of defluorination in vivo., Conclusion: The results demonstrate that [18 F]SF51 is an excellent radioligand that can quantify TSPO with a good ratio of specific to nondisplaceable uptake and has minimal radiometabolite accumulation in brain. Collectively, the results suggest that [18 F]SF51 warrants further evaluation in humans., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2023
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21. Candidate 3-benzazepine-1-ol type GluN2B receptor radioligands ( 11 C-NR2B-Me enantiomers) have high binding in cerebellum but not to σ1 receptors.
- Author
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Cai L, Liow JS, Morse CL, Telu S, Davies R, Manly LS, Zoghbi SS, Chin FT, Innis RB, and Pike VW
- Abstract
Introduction: We recently reported
11 C-NR2B-SMe ([S-methyl-11 C](R,S)-7-thiomethoxy-3-(4-(4-methyl-phenyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol) and its enantiomers as candidate radioligands for imaging the GluN2B subunit within rat N-methyl-D-aspartate receptors. However, these radioligands gave unexpectedly high and displaceable binding in rat cerebellum, possibly due to cross-reactivity with sigma-1 (σ1) receptors. This study investigated11 C-labeled enantiomers of a close analogue (7-methoxy-3-(4-(p-tolyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol; NR2B-Me) of11 C-NR2B-SMe as new candidate GluN2B radioligands. PET was used to evaluate these radioligands in rats and to assess potential cross-reactivity to σ1 receptors., Methods: NR2B-Me was assayed for binding affinity and selectivity to GluN2B in vitro.11 C-NR2B-Me and its enantiomers were prepared by Pd-mediated treatment of boronic ester precursors with11 C-iodomethane. Brain PET scans were conducted after radioligand intravenous injection into rats. Various ligands for GluN2B receptors or σ1 receptors were administered at set doses in pre-blocking or displacement experiments to assess their impact on imaging data.18 F-FTC146 and enantiomers of11 C-NR2B-SMe were used for comparison. Radiometabolites from brain and plasma were measured ex vivo and in vitro., Results: NR2B-Me enantiomers showed high GluN2B affinity and selectivity in vitro.11 C-NR2B-Me enantiomers gave high early whole rat brain uptake of radioactivity, including high uptake in cerebellum, followed by slower decline. Radioactivity in brain at 30 min ex vivo was virtually all unchanged radioligand. Only less lipophilic radiometabolites appeared in plasma. When11 C-(R)-NR2B-Me was used, three high-affinity GluN2B ligands-NR2B-SMe, Ro25-6981, and CO101,244-showed increasing pre-block of whole brain radioactivity retention with increasing dose. Two σ1 receptor antagonists, FTC146 and BD1407, were ineffective pre-blocking agents. Together, these results strongly resemble those obtained with11 C-NR2B-SMe enantiomers, except that11 C-NR2B-Me enantiomers showed faster reversibility of binding. When18 F-FTC146 was used as a radioligand, FTC146 and BD1407 showed strong pre-blocking effects whereas GluN2B ligands showed only weak blocking effects., Conclusion:11 C-NR2B-Me enantiomers showed specific binding to GluN2B receptors in rat brain in vivo. High unexpected specific binding in cerebellum was not due to σ1 receptors. Additional investigation is needed to identify the source of the high specific binding., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2023
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22. Discovery of a High-Affinity Fluoromethyl Analog of [ 11 C]5-Cyano- N -(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([ 11 C]CPPC) and Their Comparison in Mouse and Monkey as Colony-Stimulating Factor 1 Receptor Positron Emission Tomography Radioligands.
- Author
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Altomonte S, Yan X, Morse CL, Liow JS, Jenkins MD, Montero Santamaria JA, Zoghbi SS, Innis RB, and Pike VW
- Abstract
[
11 C] CPPC has been advocated as a radioligand for colony-stimulating factor 1 receptor (CSF1R) with the potential for imaging neuroinflammation in human subjects with positron emission tomography (PET). This study sought to prepare fluoro analogs of CPPC with higher affinity to provide the potential for labeling with longer-lived fluorine-18 ( t1/2 = 109.8 min) and for delivery of higher CSF1R-specific PET signal in vivo . Seven fluorine-containing analogs of CPPC were prepared and four were found to have high inhibitory potency (IC50 in low to sub-nM range) and selectivity at CSF1R comparable with CPPC itself. One of these, a 4-fluoromethyl analog ( Psa374 ), was investigated more deeply by labeling with carbon-11 ( t1/2 = 20.4 min) for PET studies in mouse and monkey. [11 C] Psa374 showed high peak uptake in monkey brain but not in mouse brain. Pharmacological challenges revealed no CSF1R-specific binding in either species at baseline. [11 C] CPPC also failed to show specific binding at baseline. Moreover, both [11 C] Psa374 and [11 C] CPPC showed brain efflux transporter substrate behavior in both species in vivo , although Psa374 did not show liability toward human efflux transporters in vitro . Further development of [11 C] Psa374 in non-human primate models of neuroinflammation with demonstration of CSF1R-specific binding would be required to warrant the fluorine-18 labeling of Psa374 with a view to possible application in human subjects., Competing Interests: The authors declare no competing financial interest., (Not subject to U.S. Copyright. Published 2023 by American Chemical Society.)- Published
- 2023
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23. Whole-Body PET Imaging in Humans Shows That 11 C-PS13 Is Selective for Cyclooxygenase-1 and Can Measure the In Vivo Potency of Nonsteroidal Antiinflammatory Drugs.
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Kim MJ, Anaya FJ, Manly LS, Lee JH, Hong J, Shrestha S, Telu S, Henry K, Santamaria JAM, Liow JS, Zanotti-Fregonara P, Shetty HU, Zoghbi SS, Pike VW, and Innis RB
- Subjects
- Animals, Humans, Cyclooxygenase 1 metabolism, Cyclooxygenase 2 metabolism, Celecoxib pharmacology, Arachidonic Acid metabolism, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cyclooxygenase 2 Inhibitors pharmacology, Aspirin pharmacology, Positron-Emission Tomography, Ketoprofen pharmacology
- Abstract
Both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) convert arachidonic acid to prostaglandin H
2 , which has proinflammatory effects. The recently developed PET radioligand11 C-PS13 has excellent in vivo selectivity for COX-1 over COX-2 in nonhuman primates. This study sought to evaluate the selectivity of11 C-PS13 binding to COX-1 in humans and assess the utility of11 C-PS13 to measure the in vivo potency of nonsteroidal antiinflammatory drugs. Methods: Baseline11 C-PS13 whole-body PET scans were obtained for 26 healthy volunteers, followed by blocked scans with ketoprofen ( n = 8), celecoxib ( n = 8), or aspirin ( n = 8). Ketoprofen is a highly potent and selective COX-1 inhibitor, celecoxib is a preferential COX-2 inhibitor, and aspirin is a selective COX-1 inhibitor with a distinct mechanism that irreversibly inhibits substrate binding. Because blood cells, including platelets and white blood cells, also contain COX-1,11 C-PS13 uptake inhibition from blood cells was measured in vitro and ex vivo (i.e., using blood obtained during PET scanning). Results: High11 C-PS13 uptake was observed in major organs with high COX-1 density, including the spleen, lungs, kidneys, and gastrointestinal tract. Ketoprofen (1-75 mg orally) blocked uptake in these organs far more effectively than did celecoxib (100-400 mg orally). On the basis of the plasma concentration to inhibit 50% of the maximum radioligand binding in the spleen (in vivo IC50 ), ketoprofen (<0.24 μM) was more than 10-fold more potent than celecoxib (>2.5 μM) as a COX-1 inhibitor, consistent with the in vitro potencies of these drugs for inhibiting COX-1. Blockade of11 C-PS13 uptake from blood cells acquired during the PET scans mirrored that in organs of the body. Aspirin (972-1,950 mg orally) blocked such a small percentage of uptake that its in vivo IC50 could not be determined. Conclusion:11 C-PS13 selectively binds to COX-1 in humans and can measure the in vivo potency of nonsteroidal antiinflammatory drugs that competitively inhibit arachidonic acid binding to COX-1. These in vivo studies, which reflect the net effect of drug absorption and metabolism in all organs of the body, demonstrated that ketoprofen had unexpectedly high potency, that celecoxib substantially inhibited COX-1, and that aspirin acetylation of COX-1 did not block binding of the representative nonsteroidal inhibitor11 C-PS13., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2023
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24. First-in-Human Evaluation of 18 F-PF-06445974, a PET Radioligand That Preferentially Labels Phosphodiesterase-4B.
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Wakabayashi Y, Stenkrona P, Arakawa R, Yan X, Van Buskirk MG, Jenkins MD, Santamaria JAM, Maresca KP, Takano A, Liow JS, Chappie TA, Varrone A, Nag S, Zhang L, Hughes ZA, Schmidt CJ, Doran SD, Mannes A, Zanotti-Fregonara P, Ooms M, Morse CL, Zoghbi SS, Halldin C, Pike VW, and Innis RB
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- Animals, Mice, Humans, ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Positron-Emission Tomography methods, Brain diagnostic imaging, Brain metabolism, Haplorhini metabolism, Radiopharmaceuticals metabolism, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Neoplasm Proteins metabolism
- Abstract
Phosphodiesterase-4 (PDE4), which metabolizes the second messenger cyclic adenosine monophosphate (cAMP), has 4 isozymes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4B and PDE4D have the highest expression in the brain and may play a role in the pathophysiology and treatment of depression and dementia. This study evaluated the properties of the newly developed PDE4B-selective radioligand
18 F-PF-06445974 in the brains of rodents, monkeys, and humans. Methods: Three monkeys and 5 healthy human volunteers underwent PET scans after intravenous injection of18 F-PF-06445974. Brain uptake was quantified as total distribution volume ( VT ) using the standard 2-tissue-compartment model and serial concentrations of parent radioligand in arterial plasma. Results:18 F-PF-06445974 readily distributed throughout monkey and human brain and had the highest binding in the thalamus. The value of VT was well identified by a 2-tissue-compartment model but increased by 10% during the terminal portions (40 and 60 min) of the monkey and human scans, respectively, consistent with radiometabolite accumulation in the brain. The average human VT values for the whole brain were 9.5 ± 2.4 mL ⋅ cm-3 Radiochromatographic analyses in knockout mice showed that 2 efflux transporters-permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP)-completely cleared the problematic radiometabolite but also partially cleared the parent radioligand from the brain. In vitro studies with the human transporters suggest that the parent radioligand was a partial substrate for BCRP and, to a lesser extent, for P-gp. Conclusion:18 F-PF-06445974 quantified PDE4B in the human brain with reasonable, but not complete, success. The gold standard compartmental method of analyzing brain and plasma data successfully identified the regional densities of PDE4B, which were widespread and highest in the thalamus, as expected. Because the radiometabolite-induced error was only about 10%, the radioligand is, in the opinion of the authors, suitable to extend to clinical studies., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2022
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25. In Vivo Evaluation of 6 Analogs of 11 C-ER176 as Candidate 18 F-Labeled Radioligands for 18-kDa Translocator Protein.
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Lee JH, Siméon FG, Liow JS, Morse CL, Gladding RL, Santamaria JAM, Henter ID, Zoghbi SS, Pike VW, and Innis RB
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- Brain diagnostic imaging, Brain metabolism, Carbon Radioisotopes metabolism, Humans, Positron-Emission Tomography methods, Quinazolines, Radiopharmaceuticals metabolism, Fluorine metabolism, Receptors, GABA metabolism
- Abstract
Because of its excellent ratio of specific to nondisplaceable uptake, the radioligand
11 C-ER176 can successfully image 18-kDa translocator protein (TSPO), a biomarker of inflammation, in the human brain and accurately quantify target density in homozygous low-affinity binders. Our laboratory sought to develop an18 F-labeled TSPO PET radioligand based on ER176 with the potential for broader distribution. This study used generic11 C labeling and in vivo performance in the monkey brain to select the most promising among 6 fluorine-containing analogs of ER176 for subsequent labeling with longer-lived18 F. Methods: Six fluorine-containing analogs of ER176-3 fluoro and 3 trifluoromethyl isomers-were synthesized and labeled by11 C methylation at the secondary amide group of the respective N -desmethyl precursor. PET imaging of the monkey brain was performed at baseline and after blockade by N -butan-2-yl-1-(2-chlorophenyl)- N -methylisoquinoline-3-carboxamide (PK11195). Uptake was quantified using radiometabolite-corrected arterial input function. The 6 candidate radioligands were ranked for performance on the basis of 2 in vivo criteria: the ratio of specific to nondisplaceable uptake (i.e., nondisplaceable binding potential [ BPND ]) and the time stability of total distribution volume ( VT ), an indirect measure of lack of radiometabolite accumulation in the brain. Results: Total TSPO binding was quantified as VT corrected for plasma free fraction ( VT / fP ) using Logan graphical analysis for all 6 radioligands. VT / fP was generally high at baseline (222 ± 178 mL·cm-3 ) and decreased by 70%-90% after preblocking with PK11195. BPND calculated using the Lassen plot was 9.6 ± 3.8; the o -fluoro radioligand exhibited the highest BPND (12.1), followed by the m -trifluoromethyl (11.7) and m -fluoro (8.1) radioligands. For all 6 radioligands, VT reached 90% of the terminal 120-min values by 70 min and remained relatively stable thereafter, with excellent identifiability (SEs < 5%), suggesting that no significant radiometabolites accumulated in the brain. Conclusion: All 6 radioligands had good BPND and good time stability of VT Among them, the o -fluoro, m -trifluoromethyl, and m -fluoro compounds were the 3 best candidates for development as radioligands with an18 F label., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2022
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26. Comparison of three novel radiotracers for GluN2B-containing NMDA receptors in non-human primates: (R) -[ 11 C]NR2B-Me, (R) -[ 18 F]of-Me-NB1, and (S) -[ 18 F]of-NB1.
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Smart K, Zheng MQ, Ahmed H, Fang H, Xu Y, Cai L, Holden D, Kapinos M, Haider A, Felchner Z, Ropchan JR, Tamagnan G, Innis RB, Pike VW, Ametamey SM, Huang Y, and Carson RE
- Subjects
- Animals, Brain diagnostic imaging, Brain metabolism, Macaca mulatta metabolism, Positron-Emission Tomography methods, Radiopharmaceuticals metabolism, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
The NMDA receptor GluN2B subunit is a target of interest in neuropsychiatric disorders but to date there is no selective radiotracer available to quantify its availability in vivo . Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: (R) -[
11 C]NR2B-Me, (R) -[18 F]OF-Me-NB1, and (S) -[18 F]OF-NB1. Plasma free fraction, metabolism, tissue distribution and kinetics, and quantitative kinetic modeling methods and parameters were evaluated in two adult rhesus macaques. Free fraction in plasma was <2% for (R) -[11 C]NR2B-Me and (R) -[18 F]OF-Me-NB1 and higher for (S) -[18 F]OF-NB1 (15%). All radiotracers showed good brain uptake and distribution throughout grey matter, with substantial (>68%) blockade across the brain by the GluN2B-targeting drug Co-101,244 (0.25 mg/kg), including in the cerebellum. Time-activity curves were well-fitted by the one-tissue compartment model, with volume of distribution values of 20-40 mL/cm3 for (R) -[11 C]NR2B-Me, 8-16 mL/cm3 for (R) -[18 F]OF-Me-NB1, and 15-35 mL/cm3 for (S) -[18 F]OF-NB1. Estimates of regional non-displaceable binding potential were in the range of 2-3 for (R) -[11 C]NR2B-Me and (S) -[18 F]-OF-NB1, and 0.5-1 for (R) -[18 F]OF-Me-NB1. Altogether, each radiotracer showed an acceptable profile for quantitative imaging of GluN2B. (S) -[18 F]OF-NB1 has particularly promising imaging characteristics for potential translation into humans. However, the source of unexpected displaceable binding in the cerebellum for each of these compounds requires further investigation.- Published
- 2022
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27. Repurposing [ 11 C]MC1 for PET Imaging of Cyclooxygenase-2 in Colorectal Cancer Xenograft Mouse Models.
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Boyle AJ, Narvaez A, Tong J, Zoghbi SS, Pike VW, Innis RB, and Vasdev N
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- Animals, Cell Line, Tumor, Cyclooxygenase 2 metabolism, Heterografts, Humans, Mice, Tissue Distribution, Colorectal Neoplasms diagnostic imaging, Colorectal Neoplasms pathology, Positron-Emission Tomography methods
- Abstract
Purpose: Cyclooxygenase-2 (COX-2) is a target for inflammation and colorectal cancer (CRC). This study evaluated the COX-2 neuro-PET radiopharmaceutical, [
11 C]MC1, in CRC xenograft mice., Procedures: [11 C]MC1 was evaluated in ICRscid mice with HT-29 and HCT-116 CRC xenografts, with high and low COX-2 expression, respectively, by immunohistochemistry, cellular uptake, dynamic PET/MR imaging, ex vivo biodistribution, and radiometabolite analysis., Results: HT-29 xenografts were well visualized with [11 C]MC1 using PET/MR. Time-activity curves revealed steady tumor radioactivity accumulation in HT-29 xenografts that plateaued from 40 to 60 min (3.07 ± 0.65 %ID/g) and was significantly reduced by pre-treatment with MC1 or celecoxib (1.62 ± 0.29 and 1.18 ± 0.21 %ID/g, respectively, p = 0.045 and p = 0.005). Radiometabolite analysis showed that [11 C]MC1 accounted for >90 % of tumor radioactivity, with <10 % in plasma, at 40 min post-injection of the radiotracer., Conclusions: [11 C]MC1 is a promising PET imaging agent for COX-2 in CRC and translation for cancer research should be considered., (© 2021. World Molecular Imaging Society.)- Published
- 2022
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28. Cyclooxygenases as Potential PET Imaging Biomarkers to Explore Neuroinflammation in Dementia.
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Kenou BV, Manly LS, Rubovits SB, Umeozulu SA, Van Buskirk MG, Zhang AS, Pike VW, Zanotti-Fregonara P, Henter ID, and Innis RB
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- Animals, Biomarkers metabolism, Cyclooxygenase 2, Isoenzymes, Neuroinflammatory Diseases, Positron-Emission Tomography methods, Alzheimer Disease, Receptors, GABA metabolism
- Abstract
The most frequently studied target of neuroinflammation using PET is 18-kDa translocator protein, but its limitations have spurred the molecular imaging community to find more promising targets. This article reviews the development of PET radioligands for cyclooxygenase (COX) subtypes 1 and 2, enzymes that catalyze the production of inflammatory prostanoids in the periphery and brain. Although both isozymes produce the same precursor compound, prostaglandin H
2 , they have distinct functions based on their differential cellular localization in the periphery and brain. For example, COX-1 is located primarily in microglia, a resident inflammatory cell in the brain whose role in producing inflammatory cytokines is well documented. In contrast, COX-2 is located primarily in neurons and can be markedly upregulated by inflammatory and excitatory stimuli, but its functions are poorly understood. This article reviews these 2 isozymes as biomarkers of neuroinflammation, as well as the radioligands that have recently been developed to image them in animals and humans. To place this work into context, the properties of COX-1 and COX-2 are compared with 18-kDa translocator protein, with special consideration of their application in Alzheimer disease as a representative neurodegenerative disorder., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2022
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29. 18 F-GE180, a failed tracer for translocator protein, has no place in child abuse imaging.
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Zanotti-Fregonara P, Rizzo G, Veronese M, Innis RB, and Turkheimer FE
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- Brain metabolism, Child, Humans, Child Abuse diagnosis, Positron-Emission Tomography methods
- Published
- 2022
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30. PET-BIDS, an extension to the brain imaging data structure for positron emission tomography.
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Norgaard M, Matheson GJ, Hansen HD, Thomas A, Searle G, Rizzo G, Veronese M, Giacomel A, Yaqub M, Tonietto M, Funck T, Gillman A, Boniface H, Routier A, Dalenberg JR, Betthauser T, Feingold F, Markiewicz CJ, Gorgolewski KJ, Blair RW, Appelhoff S, Gau R, Salo T, Niso G, Pernet C, Phillips C, Oostenveld R, Gallezot JD, Carson RE, Knudsen GM, Innis RB, and Ganz M
- Subjects
- Magnetic Resonance Imaging, Multimodal Imaging, Neuroimaging methods, Positron-Emission Tomography
- Published
- 2022
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31. Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising 18 F-Labeled Ligand.
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Siméon FG, Lee JH, Morse CL, Stukes I, Zoghbi SS, Manly LS, Liow JS, Gladding RL, Dick RM, Yan X, Taliani S, Costa B, Martini C, Da Settimo F, Castellano S, Innis RB, and Pike VW
- Subjects
- Animals, Brain diagnostic imaging, Brain metabolism, Carbon Radioisotopes chemistry, Humans, Ligands, Mice, Radiopharmaceuticals chemistry, Fluorine analysis, Positron-Emission Tomography, Radiopharmaceuticals administration & dosage, Receptors, GABA metabolism
- Abstract
Translocator protein 18 kDa (TSPO) is a biomarker of neuroinflammation. [
11 C]ER176 robustly quantifies TSPO in the human brain with positron emission tomography (PET), irrespective of subject genotype. We aimed to develop an ER176 analog with potential for labeling with longer-lived fluorine-18 ( t1/2 = 109.8 min). New fluoro and trifluoromethyl analogs of ER176 were prepared through a concise synthetic strategy. These ligands showed high TSPO affinity and low human genotype sensitivity. Each ligand was initially labeled by a generic11 C-methylation procedure, thereby enabling speedy screening in mice. Each radioligand was rapidly taken up and well retained in the mouse brain at baseline after intravenous injection. Preblocking of TSPO showed that high proportions of brain uptake were specifically bound to TSPO at baseline. Overall, the 3-fluoro analog of [11 C]ER176 ([11 C] 3b ) displayed the most promising imaging properties. Therefore, a method was developed to label 3b with [18 F]fluoride ion. [18 F] 3b gave similarly promising PET imaging results and deserves evaluation in higher species.- Published
- 2021
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32. [ 11 C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain.
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Yan X, Telu S, Dick RM, Liow JS, Zanotti-Fregonara P, Morse CL, Manly LS, Gladding RL, Shrestha S, Lerchner W, Nagai Y, Minamimoto T, Zoghbi SS, Innis RB, Pike VW, Richmond BJ, and Eldridge MA
- Subjects
- Animals, Cholinergic Agents metabolism, Clozapine pharmacology, Macaca mulatta, Male, Piperazines pharmacology, Transfection, Clozapine therapeutic use, Positron-Emission Tomography methods, Radioligand Assay methods
- Abstract
Previous work found that [
11 C]deschloroclozapine ([11 C]DCZ) is superior to [11 C]clozapine ([11 C]CLZ) for imaging Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This study used PET to quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions to better understand this superiority. A genetically-modified muscarinic type-4 human receptor (hM4 Di) was injected into the right amygdala of a male rhesus macaque. [11 C]DCZ and [11 C]CLZ PET scans were conducted 2-24 months later. Uptake was quantified relative to the concentration of parent radioligand in arterial plasma at baseline (n = 3 scans/radioligand) and after receptor blockade (n = 3 scans/radioligand). Both radioligands had greater uptake in the transfected region and displaceable uptake in other brain regions. Displaceable uptake was not uniformly distributed, perhaps representing off-target binding to endogenous receptor(s). After correction, [11 C]DCZ signal was 19% of that for [11 C]CLZ, and background uptake was 10% of that for [11 C]CLZ. Despite stronger [11 C]CLZ binding, the signal-to-background ratio for [11 C]DCZ was almost two-fold greater than for [11 C]CLZ. Both radioligands had comparable DREADD selectivity. All reference tissue models underestimated signal-to-background ratio in the transfected region by 40%-50% for both radioligands. Thus, the greater signal-to-background ratio of [11 C]DCZ was due to its lower background uptake.- Published
- 2021
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33. Repurposing 11 C-PS13 for PET Imaging of Cyclooxygenase-1 in Ovarian Cancer Xenograft Mouse Models.
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Boyle AJ, Tong J, Zoghbi SS, Pike VW, Innis RB, and Vasdev N
- Subjects
- Animals, Cell Line, Tumor, Female, Humans, Mice, Ovarian Neoplasms diagnostic imaging, Ovarian Neoplasms metabolism, Carbon Radioisotopes, Cell Transformation, Neoplastic, Cyclooxygenase 1 metabolism, Drug Repositioning, Ovarian Neoplasms pathology, Positron-Emission Tomography
- Abstract
Cyclooxygenase-1 (COX-1), a biomarker for neuroinflammation, is implicated in the progression and prognosis of ovarian cancer (OvCa). This study considered the repurposing of
11 C-labeled 1,5-bis(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1 H -1,2,4-triazole (11 C-PS13), a COX-1 PET neuroimaging radiopharmaceutical, in OvCa xenograft mouse models. Methods:11 C-PS13 was evaluated in ICRscid mice with subcutaneous or intraperitoneal human OVCAR-3 OvCa xenografts by dynamic PET/MRI, ex vivo biodistribution, and radiometabolite analysis of plasma and tumor. Results: OVCAR-3 xenografts were well visualized with11 C-PS13 in xenograft mouse models. Time-activity curves revealed a steady accumulation of tumor radioactivity that plateaued from 40 to 60 min and was significantly reduced by pretreatment with ketoprofen (3.56 ± 0.81 and 1.30 ± 0.18 percentage injected dose/g without and with pretreatment, respectively, P = 0.01). Radiometabolite analysis showed that intact11 C-PS13 accounted for more than 80% of radioactivity in the tumor, with less than 20% in plasma, at 40 min after injection. Conclusion:11 C-PS13 shows promise for PET imaging of COX-1 in OvCa, and rapid translation for clinical cancer research should be considered., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2021
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34. In vitro and pilot in vivo imaging of 18 kDa translocator protein (TSPO) in inflammatory vascular disease.
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Schollhammer R, Lepreux S, Barthe N, Vimont D, Rullier A, Sibon I, Berard X, Zhang A, Kimura Y, Fujita M, Innis RB, Zanotti-Fregonara P, and Morgat C
- Abstract
Background: Inflammatory vascular disease of the arteries, such as inflamed atheromatous plaques or arteritis, may cause aneurysms or ischemic strokes. In this context, using positron emission tomography (PET) to image inflammation may help select patients who would benefit from appropriate therapeutic interventions. This study sought to assess the usefulness of the 18 kDa translocator protein (TSPO) tracers [
11 C]-PBR28 and [18 F]-PBR06 for imaging inflammatory vascular disease in vitro and in vivo. Immunohistochemistry for macrophage infiltration as well as autoradiography with [18 F]-PBR06 were performed on eight paraffin-embedded, formalin-fixed atherosclerosis plaques prospectively collected after carotid endarterectomy of eight patients affected by ischemic stroke. Six different patients, one of whom was also included in the in vitro study, underwent PET imaging. Two patients with carotid stenosis associated with ischemic stroke were imaged with [18 F]-PBR06 PET/CT, and four other patients (three with large vessel vasculitis and one with bilateral carotid stenosis but without stroke) were imaged with [11 C]-PBR28., Results: All in vitro sections showed specific binding of [18 F]-PBR06, which co-localized with immunohistochemistry markers for inflammation. However, in vivo TSPO imaging with either [11 C]-PBR28 or [18 F]-PBR06 was negative in all participants., Conclusion: Despite good uptake on surgical samples in vitro, [11 C]-PBR28 and [18 F]-PBR06 are not viable clinical tools for imaging inflammatory vascular disease., Trial Registration: NCT02513589, registered 31 July 2015 and NCT00547976, registered 23 October 2007. https://clinicaltrials.gov .- Published
- 2021
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35. Functional Selectivity of a Biased Cannabinoid-1 Receptor (CB 1 R) Antagonist.
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Liu Z, Iyer MR, Godlewski G, Jourdan T, Liu J, Coffey NJ, Zawatsky CN, Puhl HL, Wess J, Meister J, Liow JS, Innis RB, Hassan SA, Lee YS, Kunos G, and Cinar R
- Abstract
Seven-transmembrane receptors signal via G-protein- and β-arrestin-dependent pathways. We describe a peripheral CB
1 R antagonist (MRI-1891) highly biased toward inhibiting CB1 R-induced β-arrestin-2 (βArr2) recruitment over G-protein activation. In obese wild-type and βArr2-knockout (KO) mice, MRI-1891 treatment reduces food intake and body weight without eliciting anxiety even at a high dose causing partial brain CB1 R occupancy. By contrast, the unbiased global CB1 R antagonist rimonabant elicits anxiety in both strains, indicating no βArr2 involvement. Interestingly, obesity-induced muscle insulin resistance is improved by MRI-1891 in wild-type but not in βArr2-KO mice. In C2C12 myoblasts, CB1 R activation suppresses insulin-induced akt-2 phosphorylation, preventable by MRI-1891, βArr2 knockdown or overexpression of CB1 R-interacting protein. MRI-1891, but not rimonabant, interacts with nonpolar residues on the N-terminal loop, including F108, and on transmembrane helix-1, including S123, a combination that facilitates βArr2 bias. Thus, CB1 R promotes muscle insulin resistance via βArr2 signaling, selectively mitigated by a biased CB1 R antagonist at reduced risk of central nervous system (CNS) side effects., Competing Interests: The authors declare the following competing financial interest(s): G.K., R.C., and M.R.I. are listed as co-inventors on two US Government patents covering (S)-MRI-1891. The remaining authors declare no competing interests., (Not subject to U.S. Copyright. Published 2021 by American Chemical Society.)- Published
- 2021
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36. Region- and voxel-based quantification in human brain of [ 18 F]LSN3316612, a radioligand for O-GlcNAcase.
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Lee JH, Veronese M, Liow JS, Morse CL, Montero Santamaria JA, Haskali MB, Zoghbi SS, Pike VW, Innis RB, and Zanotti-Fregonara P
- Abstract
Background: Previous studies found that the positron emission tomography (PET) radioligand [
18 F]LSN3316612 accurately quantified O-GlcNAcase in human brain using a two-tissue compartment model (2TCM). This study sought to assess kinetic model(s) as an alternative to 2TCM for quantifying [18 F]LSN3316612 binding, particularly in order to generate good-quality parametric images., Methods: The current study reanalyzed data from a previous study of 10 healthy volunteers who underwent both test and retest PET scans with [18 F]LSN3316612. Kinetic analysis was performed at the region level with 2TCM using 120-min PET data and arterial input function, which was considered as the gold standard. Quantification was then obtained at both the region and voxel levels using Logan plot, Ichise's multilinear analysis-1 (MA1), standard spectral analysis (SA), and impulse response function at 120 min (IRF120 ). To avoid arterial sampling, a noninvasive relative quantification (standardized uptake value ratio (SUVR)) was also tested using the corpus callosum as a pseudo-reference region. Venous samples were also assessed to see whether they could substitute for arterial ones., Results: Logan and MA1 generated parametric images of good visual quality and their total distribution volume (VT ) values at both the region and voxel levels were strongly correlated with 2TCM-derived VT (r = 0.96-0.99) and showed little bias (up to - 8%). SA was more weakly correlated to 2TCM-derived VT (r = 0.93-0.98) and was more biased (~ 16%). IRF120 showed a strong correlation with 2TCM-derived VT (r = 0.96) but generated noisier parametric images. All techniques were comparable to 2TCM in terms of test-retest variability and reliability except IRF120 , which gave significantly worse results. Noninvasive SUVR values were not correlated with 2TCM-derived VT , and arteriovenous equilibrium was never reached., Conclusions: Compared to SA and IRF, Logan and MA1 are more suitable alternatives to 2TCM for quantifying [18 F]LSN3316612 and generating good-quality parametric images.- Published
- 2021
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37. Synthesis of [ 18 F]PS13 and Evaluation as a PET Radioligand for Cyclooxygenase-1 in Monkey.
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Taddei C, Morse CL, Kim MJ, Liow JS, Montero Santamaria J, Zhang A, Manly LS, Zanotti-Fregonara P, Gladding RL, Zoghbi SS, Innis RB, and Pike VW
- Subjects
- Animals, Brain diagnostic imaging, Brain metabolism, Carbon Radioisotopes, Cyclooxygenase 1 metabolism, Positron-Emission Tomography, Radiopharmaceuticals, Fluorides, Fluorine Radioisotopes
- Abstract
Cyclooxygenase-1 (COX-1) and its isozyme COX-2 are key enzymes in the syntheses of prostanoids. Imaging of COX-1 and COX-2 selective radioligands with positron emission tomography (PET) may clarify how these enzymes are involved in inflammatory conditions and assist in the discovery of improved anti-inflammatory drugs. We have previously labeled the selective high-affinity COX-1 ligand, 1,5-bis(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1 H -1,2,4-triazole (PS13), with carbon-11 ( t
1/2 = 20.4 min). This radioligand ([11 C]PS13) has been successful for PET imaging of COX-1 in monkey and human brain and in periphery. [11 C]PS13 is being used in clinical investigations. Alternative labeling of PS13 with fluorine-18 ( t1/2 = 109.8 min) is desirable to provide a longer-lived radioligand in high activity that might be readily distributed among imaging centers. However, labeling of PS13 in its 1,1,1-trifluoroethoxy group is a radiochemical challenge. Here we assess two labeling approaches based on nucleophilic addition of cyclotron-produced [18 F]fluoride ion to gem -difluorovinyl precursors, either to label PS13 in one step or to produce [18 F]2,2,2-trifluoroethyl p- toluenesulfonate for labeling a hydroxyl precursor. From the latter two-step approach, we obtained [18 F]PS13 ready for intravenous injection in a decay-corrected radiochemical yield of 7.9% and with a molar activity of up to 7.9 GBq/μmol. PET imaging of monkey brain with [18 F]PS13 shows that this radioligand can specifically image and quantify COX-1 without radiodefluorination but with some radioactivity uptake in skull, ascribed to red bone marrow. The development of a new procedure for labeling PS13 with fluorine-18 at a higher molar activity is, however, desirable to suppress occupancy of COX-1 by carrier at baseline.- Published
- 2021
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38. 11 C Dosimetry Scans Should Be Abandoned.
- Author
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Zanotti-Fregonara P, Lammertsma AA, and Innis RB
- Subjects
- Humans, Positron-Emission Tomography, Carbon Radioisotopes, Radiometry
- Published
- 2021
- Full Text
- View/download PDF
39. Neuroinflammation in psychiatric disorders: PET imaging and promising new targets.
- Author
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Meyer JH, Cervenka S, Kim MJ, Kreisl WC, Henter ID, and Innis RB
- Subjects
- Animals, Biomarkers metabolism, Brain pathology, Humans, Brain diagnostic imaging, Inflammation diagnostic imaging, Mental Disorders diagnostic imaging, Positron-Emission Tomography, Receptors, GABA metabolism
- Abstract
Neuroinflammation is a multifaceted physiological and pathophysiological response of the brain to injury and disease. Given imaging findings of 18 kDa translocator protein (TSPO) and the development of radioligands for other inflammatory targets, PET imaging of neuroinflammation is at a particularly promising stage. This Review critically evaluates PET imaging results of inflammation in psychiatric disorders, including major depressive disorder, schizophrenia and psychosis disorders, substance use, and obsessive-compulsive disorder. We also consider promising new targets that can be measured in the brain, such as monoamine oxidase B, cyclooxygenase-1 and cyclooxygenase-2, colony stimulating factor 1 receptor, and the purinergic P2X7 receptor. Thus far, the most compelling TSPO imaging results have arguably been found in major depressive disorder, for which consistent increases have been observed, and in schizophrenia and psychosis, for which patients show reduced TSPO levels. This pattern highlights the importance of validating brain biomarkers of neuroinflammation for each condition separately before moving on to patient stratification and treatment monitoring trials., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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40. First-in-human evaluation of [ 11 C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain.
- Author
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Kim MJ, Lee JH, Juarez Anaya F, Hong J, Miller W, Telu S, Singh P, Cortes MY, Henry K, Tye GL, Frankland MP, Montero Santamaria JA, Liow JS, Zoghbi SS, Fujita M, Pike VW, and Innis RB
- Subjects
- Animals, Cyclooxygenase 1 metabolism, Humans, Radiopharmaceuticals, Reproducibility of Results, Brain diagnostic imaging, Brain metabolism, Positron-Emission Tomography
- Abstract
Purpose: This study assessed whether the newly developed PET radioligand [
11 C]PS13, which has shown excellent in vivo selectivity in previous animal studies, could be used to quantify constitutive levels of cyclooxygenase-1 (COX-1) in healthy human brain., Methods: Brain test-retest scans with concurrent arterial blood samples were obtained in 10 healthy individuals. The one- and unconstrained two-tissue compartment models, as well as the Logan graphical analysis were compared, and test-retest reliability and time-stability of total distribution volume (VT ) were assessed. Correlation analyses were conducted between brain regional VT and COX-1 transcript levels provided in the Allen Human Brain Atlas., Results: In the brain, [11 C]PS13 showed highest uptake in the hippocampus and occipital cortex. The pericentral cortex also showed relatively higher uptake compared with adjacent neocortices. The two-tissue compartment model showed the best fit in all the brain regions, and the results from the Logan graphical analysis were consistent with those from the two-tissue compartment model. VT values showed excellent test-retest variability (range 6.0-8.5%) and good reliability (intraclass correlation coefficient range 0.74-0.87). VT values also showed excellent time-stability in all brain regions, confirming that there was no radiometabolite accumulation and that shorter scans were still able to reliably measure VT . Significant correlation was observed between VT and COX-1 transcript levels (r = 0.82, P = 0.007), indicating that [11 C]PS13 binding reflects actual COX-1 density in the human brain., Conclusions: These results from the first-in-human evaluation of the ability of [11 C]PS13 to image COX-1 in the brain justifies extending the study to disease populations with neuroinflammation., Clinical Trial Registration: NCT03324646 at https://clinicaltrials.gov/ . Registered October 30, 2017. Retrospectively registered.- Published
- 2020
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41. PET Imaging of Phosphodiesterase-4 Identifies Affected Dysplastic Bone in McCune-Albright Syndrome, a Genetic Mosaic Disorder.
- Author
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Weidner LD, Wakabayashi Y, Stolz LA, Collins MT, Guthrie L, Victorino M, Chung J, Miller W, Zoghbi SS, Pike VW, Fujita M, Innis RB, and Boyce AM
- Subjects
- Adult, Bone and Bones pathology, Brain diagnostic imaging, Female, Humans, Male, Whole Body Imaging, Bone and Bones diagnostic imaging, Carbon Radioisotopes pharmacokinetics, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Fibrous Dysplasia, Polyostotic diagnostic imaging, Positron-Emission Tomography methods, Rolipram pharmacokinetics
- Abstract
McCune-Albright syndrome (MAS) is a mosaic disorder arising from gain-of-function mutations in the GNAS gene, which encodes the 3',5'-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, G
s α. Clinical manifestations of MAS in a given individual, including fibrous dysplasia, are determined by the timing and location of the GNAS mutation during embryogenesis, the tissues involved, and the role of Gs α in the affected tissues. The Gs α mutation results in dysregulation of the cAMP signaling cascade, leading to upregulation of phosphodiesterase type 4 (PDE4), which catalyzes the hydrolysis of cAMP. Increased cAMP levels have been found in vitro in both animal models of fibrous dysplasia and in cultured cells from individuals with MAS but not in humans with fibrous dysplasia. PET imaging of PDE4 with11 C-( R )-rolipram has been used successfully to study the in vivo activity of the cAMP cascade. To date, it remains unknown whether fibrous dysplasia and other symptoms of MAS, including neuropsychiatric impairments, are associated with increased PDE4 activity in humans. Methods:11 C-( R )-rolipram whole-body and brain PET scans were performed on 6 individuals with MAS (3 for brain scans and 6 for whole-body scans) and 9 healthy controls (7 for brain scans and 6 for whole-body scans). Results:11 C-( R )-rolipram binding correlated with known locations of fibrous dysplasia in the periphery of individuals with MAS; no uptake was observed in the bones of healthy controls. In peripheral organs and the brain, no difference in11 C-( R )-rolipram uptake was noted between participants with MAS and healthy controls. Conclusion: This study is the first to find evidence for increased cAMP activity in areas of fibrous dysplasia in vivo. No differences in brain uptake between MAS participants and controls were detected-a finding that could be due to several reasons, including the limited anatomic resolution of PET. Nevertheless, the results confirm the usefulness of PET scans with11 C-( R )-rolipram to indirectly measure increased cAMP pathway activation in human disease., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2020
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42. PET imaging of neuroinflammation in neurological disorders.
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Kreisl WC, Kim MJ, Coughlin JM, Henter ID, Owen DR, and Innis RB
- Subjects
- Animals, Astrocytes metabolism, Astrocytes pathology, Humans, Inflammation diagnostic imaging, Inflammation metabolism, Microglia metabolism, Brain diagnostic imaging, Brain metabolism, Nervous System Diseases diagnostic imaging, Nervous System Diseases metabolism, Positron-Emission Tomography methods
- Abstract
A growing need exists for reliable in-vivo measurement of neuroinflammation to better characterise the inflammatory processes underlying various diseases and to inform the development of novel therapeutics that target deleterious glial activity. PET is well suited to quantify neuroinflammation and has the potential to discriminate components of the neuroimmune response. However, there are several obstacles to the reliable quantification of neuroinflammation by PET imaging. Despite these challenges, PET studies have consistently identified associations between neuroimmune responses and pathophysiology in brain disorders such as Alzheimer's disease. Tissue studies have also begun to clarify the meaning of changes in PET signal in some diseases. Furthermore, although PET imaging of neuroinflammation does not have an established clinical application, novel targets are under investigation and a small but growing number of studies have suggested that this imaging modality could have a role in drug development. Future studies are needed to further improve our knowledge of the cellular mechanisms that underlie changes in PET signal, how immune response contributes to neurological disease, and how it might be therapeutically modified., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
- Full Text
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43. Development of a non-radiometric method for measuring the arterial input function of a 11 C-labeled PET radiotracer.
- Author
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Shetty HU, Zoghbi SS, Morse CL, Kowalski A, Hirvonen J, Innis RB, and Pike VW
- Subjects
- Algorithms, Arteries physiology, Carbon Radioisotopes blood, Carbon Radioisotopes pharmacokinetics, Chromatography, Liquid, Half-Life, Humans, Radiometry, Radiopharmaceuticals blood, Radiopharmaceuticals pharmacokinetics, Tandem Mass Spectrometry, Arteries diagnostic imaging, Carbon Radioisotopes administration & dosage, Positron-Emission Tomography methods, Radiopharmaceuticals administration & dosage
- Abstract
Positron emission tomography (PET) uses radiotracers to quantify important biochemical parameters in human subjects. A radiotracer arterial input function (AIF) is often essential for converting brain PET data into robust output measures. For radiotracers labeled with carbon-11 (t
1/2 = 20.4 min), AIF is routinely determined with radio-HPLC of blood sampled frequently during the PET experiment. There has been no alternative to this logistically demanding method, neither for regular use nor validation. A11 C-labeled tracer is always accompanied by a large excess of non-radioactive tracer known as carrier. In principle, AIF might be obtained by measuring the molar activity (Am ; ratio of radioactivity to total mass; Bq/mol) of a radiotracer dose and the time-course of carrier concentration in plasma after radiotracer injection. Here, we implement this principle in a new method for determining AIF, as shown by using [11 C]PBR28 as a representative tracer. The method uses liquid chromatography-tandem mass spectrometry for measuring radiotracer Am and then the carrier in plasma sampled regularly over the course of a PET experiment. Am and AIF were determined radiometrically for comparison. The new non-radiometric method is not constrained by the short half-life of carbon-11 and is an attractive alternative to conventional AIF measurement.- Published
- 2020
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44. Evaluation of 11 C-NR2B-SMe and Its Enantiomers as PET Radioligands for Imaging the NR2B Subunit Within the NMDA Receptor Complex in Rats.
- Author
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Cai L, Liow JS, Morse CL, Telu S, Davies R, Frankland MP, Zoghbi SS, Cheng K, Hall MD, Innis RB, and Pike VW
- Subjects
- Animals, Ligands, Rats, Stereoisomerism, Positron-Emission Tomography methods, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
[ S - methyl -
11 C](±)-7-methoxy-3-(4-(4-(methylthio)phenyl)butyl)-2,3,4,5-tetrahydro-1 H -benzo[ d ]azepin-1-ol (11 C-NR2B-SMe) and its enantiomers were synthesized as candidates for imaging the NR2B subunit within the N -methyl-d-aspartate receptor with PET. Methods: Brains were scanned with PET for 90 min after intravenous injection of one of the candidate radioligands into rats. To detect any NR2B-specific binding of radioligand in brain, various preblocking or displacing agents were evaluated for their impact on the PET brain imaging data. Radiometabolites from brain and other tissues were measured ex vivo and in vitro. Results: Each radioligand gave high early whole-brain uptake of radioactivity, followed by a brief fast decline and then a slow final decline.11 C-( S )-NR2B-SMe was studied extensively. Ex vivo measurements showed that radioactivity in rat brain at 30 min after radioligand injection was virtually unchanged radioligand. Only less lipophilic radiometabolites appeared in plasma. High-affinity NR2B ligands, Ro-25-6981, ifenprodil, and CO101244, showed increasing preblocking of whole-brain radioactivity retention with increasing dose (0.01-3.00 mg/kg, intravenously). Five σ1 antagonists (FTC146, BD1407, F3, F4, and NE100) and 4 σ1 agonists ((+)-pentazocine, (±)-PPCC, PRE-084, and (+)-SKF10047) were ineffective preblocking agents, except FTC146 and F4 at a high dose. Two potent σ1 receptor agonists, TC1 and SA4503, showed dose-dependent preblocking effects in the presence or absence of pharmacologic σ1 receptor blockade with FTC146. Conclusion:11 C-( S )-NR2B-SMe has adequate NR2B-specific PET signal in rat brain to warrant further evaluation in higher species. TC1 and SA4503 likely have off-target binding to NR2B in vivo., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2020
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45. Guidelines for the content and format of PET brain data in publications and archives: A consensus paper.
- Author
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Knudsen GM, Ganz M, Appelhoff S, Boellaard R, Bormans G, Carson RE, Catana C, Doudet D, Gee AD, Greve DN, Gunn RN, Halldin C, Herscovitch P, Huang H, Keller SH, Lammertsma AA, Lanzenberger R, Liow JS, Lohith TG, Lubberink M, Lyoo CH, Mann JJ, Matheson GJ, Nichols TE, Nørgaard M, Ogden T, Parsey R, Pike VW, Price J, Rizzo G, Rosa-Neto P, Schain M, Scott PJ, Searle G, Slifstein M, Suhara T, Talbot PS, Thomas A, Veronese M, Wong DF, Yaqub M, Zanderigo F, Zoghbi S, and Innis RB
- Subjects
- Consensus, Fluorodeoxyglucose F18, Humans, Image Processing, Computer-Assisted standards, Neuroimaging standards, Positron-Emission Tomography standards, Radiopharmaceuticals, Reproducibility of Results, Brain diagnostic imaging, Image Processing, Computer-Assisted methods, Neuroimaging methods, Positron-Emission Tomography methods, Practice Guidelines as Topic
- Abstract
It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.
- Published
- 2020
- Full Text
- View/download PDF
46. PET ligands [ 18 F]LSN3316612 and [ 11 C]LSN3316612 quantify O -linked-β- N -acetyl-glucosamine hydrolase in the brain.
- Author
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Lu S, Haskali MB, Ruley KM, Dreyfus NJ, DuBois SL, Paul S, Liow JS, Morse CL, Kowalski A, Gladding RL, Gilmore J, Mogg AJ, Morin SM, Lindsay-Scott PJ, Ruble JC, Kant NA, Shcherbinin S, Barth VN, Johnson MP, Cuadrado M, Jambrina E, Mannes AJ, Nuthall HN, Zoghbi SS, Jesudason CD, Innis RB, and Pike VW
- Subjects
- Animals, Brain diagnostic imaging, Brain metabolism, Glucosamine, Ligands, Positron-Emission Tomography, Rats, Hydrolases, beta-N-Acetylhexosaminidases metabolism
- Abstract
We aimed to develop effective radioligands for quantifying brain O -linked-β- N -acetyl-glucosamine ( O -GlcNAc) hydrolase (OGA) using positron emission tomography in living subjects as tools for evaluating drug target engagement. Posttranslational modifications of tau, a biomarker of Alzheimer's disease, by O -GlcNAc through the enzyme pair OGA and O -GlcNAc transferase (OGT) are inversely related to the amounts of its insoluble hyperphosphorylated form. Increase in tau O -GlcNAcylation by OGA inhibition is believed to reduce tau aggregation. LSN3316612, a highly selective and potent OGA ligand [half-maximal inhibitory concentration (IC
50 ) = 1.9 nM], emerged as a lead ligand after in silico analysis and in vitro evaluations. [3 H]LSN3316612 imaged and quantified OGA in postmortem brains of rat, monkey, and human. The presence of fluorine and carbonyl functionality in LSN3316612 enabled labeling with positron-emitting fluorine-18 or carbon-11. Both [18 F]LSN3316612 and [11 C]LSN3316612 bound reversibly to OGA in vivo, and such binding was blocked by pharmacological doses of thiamet G, an OGA inhibitor of different chemotype, in monkeys. [18 F]LSN3316612 entered healthy human brain avidly (~4 SUV) without radiodefluorination or adverse effect from other radiometabolites, as evidenced by stable brain total volume of distribution (VT ) values by 110 min of scanning. Overall, [18 F]LSN3316612 is preferred over [11 C]LSN3316612 for future human studies, whereas either may be an effective positron emission tomography radioligand for quantifying brain OGA in rodent and monkey., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2020
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47. Discovery, Radiolabeling, and Evaluation of Subtype-Selective Inhibitors for Positron Emission Tomography Imaging of Brain Phosphodiesterase-4D.
- Author
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Wakabayashi Y, Telu S, Dick RM, Fujita M, Ooms M, Morse CL, Liow JS, Hong JS, Gladding RL, Manly LS, Zoghbi SS, Mo X, D'Amato EC, Sindac JA, Nugent RA, Marron BE, Gurney ME, Innis RB, and Pike VW
- Subjects
- Carbon Radioisotopes, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Radiopharmaceuticals, Rolipram pharmacology, Brain diagnostic imaging, Brain metabolism, Positron-Emission Tomography
- Abstract
We aimed to develop radioligands for PET imaging of brain phosphodiesterase subtype 4D (PDE4D), a potential target for developing cognition enhancing or antidepressive drugs. Exploration of several chemical series gave four leads with high PDE4D inhibitory potency and selectivity, optimal lipophilicity, and good brain uptake. These leads featured alkoxypyridinyl cores. They were successfully labeled with carbon-11 ( t
1/2 = 20.4 min) for evaluation with PET in monkey. Whereas two of these radioligands did not provide PDE4D-specific signal in monkey brain, two others, [11 C]T1660 and [11 C]T1650, provided sizable specific signal, as judged by pharmacological challenge using rolipram or a selective PDE4D inhibitor (BPN14770) and subsequent biomathematical analysis. Specific binding was highest in prefrontal cortex, temporal cortex, and hippocampus, regions that are important for cognitive function. [11 C]T1650 was progressed to evaluation in humans with PET, but the output measure of brain enzyme density ( VT ) increased with scan duration. This instability over time suggests that radiometabolite(s) were accumulating in the brain. BPN14770 blocked PDE4D uptake in human brain after a single dose, but the percentage occupancy was difficult to estimate because of the unreliability of measuring VT . Overall, these results show that imaging of PDE4D in primate brain is feasible but that further radioligand refinement is needed, most likely to avoid problematic radiometabolites.- Published
- 2020
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48. PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study.
- Author
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Shrestha S, Kim MJ, Eldridge M, Lehmann ML, Frankland M, Liow JS, Yu ZX, Cortes-Salva M, Telu S, Henter ID, Gallagher E, Lee JH, Fredericks JM, Poffenberger C, Tye G, Ruiz-Perdomo Y, Anaya FJ, Montero Santamaria JA, Gladding RL, Zoghbi SS, Fujita M, Katz JD, Pike VW, and Innis RB
- Subjects
- Adult, Animals, Arthritis, Rheumatoid diagnostic imaging, Brain diagnostic imaging, Female, Humans, Macaca mulatta, Middle Aged, Cyclooxygenase 2 analysis, Inflammation diagnostic imaging, Positron-Emission Tomography methods, Pyrimidines, Radiopharmaceuticals
- Abstract
Background: Cyclooxygenase-2 (COX-2), which is rapidly upregulated by inflammation, is a key enzyme catalyzing the rate-limiting step in the synthesis of several inflammatory prostanoids. Successful positron emission tomography (PET) radioligand imaging of COX-2 in vivo could be a potentially powerful tool for assessing inflammatory response in the brain and periphery. To date, however, the development of PET radioligands for COX-2 has had limited success., Methods: The novel PET tracer [
11 C]MC1 was used to examine COX-2 expression [1] in the brains of four rhesus macaques at baseline and after injection of the inflammogen lipopolysaccharide (LPS) into the right putamen, and [2] in the joints of two human participants with rheumatoid arthritis and two healthy individuals. In the primate study, two monkeys had one LPS injection, and two monkeys had a second injection 33 and 44 days, respectively, after the first LPS injection. As a comparator, COX-1 expression was measured using [11 C]PS13., Results: COX-2 binding, expressed as the ratio of specific to nondisplaceable uptake (BPND ) of [11 C]MC1, increased on day 1 post-LPS injection; no such increase in COX-1 expression, measured using [11 C]PS13, was observed. The day after the second LPS injection, a brain lesion (~ 0.5 cm in diameter) with high COX-2 density and high BPND (1.8) was observed. Postmortem brain analysis at the gene transcript or protein level confirmed in vivo PET results. An incidental finding in an unrelated monkey found a line of COX-2 positivity along an incision in skull muscle, demonstrating that [11 C]MC1 can localize inflammation peripheral to the brain. In patients with rheumatoid arthritis, [11 C]MC1 successfully imaged upregulated COX-2 in the arthritic hand and shoulder and apparently in the brain. Uptake was blocked by celecoxib, a COX-2 preferential inhibitor., Conclusions: Taken together, these results indicate that [11 C]MC1 can image and quantify COX-2 upregulation in both monkey brain after LPS-induced neuroinflammation and in human peripheral tissue with inflammation., Trial Registration: ClinicalTrials.gov NCT03912428. Registered April 11, 2019.- Published
- 2020
- Full Text
- View/download PDF
49. PET quantification of brain O-GlcNAcase with [ 18 F]LSN3316612 in healthy human volunteers.
- Author
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Lee JH, Liow JS, Paul S, Morse CL, Haskali MB, Manly L, Shcherbinin S, Ruble JC, Kant N, Collins EC, Nuthall HN, Zanotti-Fregonara P, Zoghbi SS, Pike VW, and Innis RB
- Abstract
Background: Previous studies found that [
18 F]LSN3316612 was a promising positron emission tomography (PET) radioligand for imaging O-GlcNAcase in nonhuman primates and human volunteers. This study sought to further evaluate the suitability of [18 F]LSN3316612 for human clinical research., Methods: Kinetic evaluation of [18 F]LSN3316612 was conducted in a combined set of baseline brain scans from 17 healthy human volunteers and test-retest imaging was conducted in 10 of these volunteers; another 6 volunteers had whole-body scans to measure radiation exposure to body organs. Total distribution volume (VT ) estimates were compared for the one- and two-tissue compartment models with the arterial input function. Test-retest variability and reliability were evaluated via mean difference and intraclass correlation coefficient (ICC). The time stability of VT was assessed down to a 30-min scan time. An alternative quantification method for [18 F]LSN3316612 binding without blood was also investigated to assess the possibility of eliminating arterial sampling., Results: Brain uptake was generally high and could be quantified as VT with excellent identifiability using the two-tissue compartment model. [18 F]LSN3316612 exhibited good absolute test-retest variability (12.5%), but the arithmetic test-retest variability was far from 0 (11.3%), reflecting a near-uniform increase of VT on the retest scan in nine of 10 volunteers. VT values were stable after 110 min in all brain regions, suggesting that no radiometabolites accumulated in the brain. Measurements obtained using only brain activity (i.e., area under the curve (AUC) from 150-180 min) correlated strongly with regional VT values during test-retest conditions (R2 = 0.84), exhibiting similar reliability to VT (ICC = 0.68 vs. 0.64). Estimated radiation exposure for [18 F]LSN3316612 PET was 20.5 ± 2.1 μSv/MBq, comparable to other18 F-labeled radioligands for brain imaging., Conclusions: [18 F]LSN3316612 is an excellent PET radioligand for imaging O-GlcNAcase in the human brain. Alternative quantification without blood is possible, at least for within-subject repeat studies. However, the unexplained increase of VT under retest conditions requires further investigation.- Published
- 2020
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50. Automatic Extraction of a Reference Region for the Noninvasive Quantification of Translocator Protein in Brain Using 11 C-PBR28.
- Author
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Zanotti-Fregonara P, Kreisl WC, Innis RB, and Lyoo CH
- Subjects
- Alzheimer Disease diagnostic imaging, Alzheimer Disease metabolism, Automation, Case-Control Studies, Cognitive Dysfunction diagnostic imaging, Cognitive Dysfunction metabolism, Humans, Kinetics, Magnetic Resonance Imaging, Models, Biological, Positron-Emission Tomography, Brain diagnostic imaging, Brain metabolism, Image Processing, Computer-Assisted methods, Pyrimidines, Receptors, GABA metabolism
- Abstract
Brain inflammation is associated with various types of neurodegenerative diseases, including Alzheimer disease (AD). Quantifying inflammation with PET is a challenging and invasive procedure, especially in frail patients, because it requires blood sampling from an arterial catheter. A widely used alternative to arterial sampling is a supervised clustering algorithm (SVCA), which identifies the voxels with minimal specific binding in the PET images, thus extracting a reference region for noninvasive kinetic modeling. Methods: We tested this algorithm on a large population of subjects injected with the translocator protein radioligand
11 C-PBR28 and compared the kinetic modeling results obtained with the gold standard of arterial input function ( VT / fp ) with those obtained by SVCA (distribution volume ratio [DVR] with Logan plot). The study comprised 57 participants (21 healthy controls, 11 mild cognitive impairment patients, and 25 AD patients). Results: We found that VT / fp was greater in AD patients than in controls in the inferior parietal, combined middle and inferior temporal, and entorhinal cortices. SVCA-DVR identified increased binding in the same regions and in an additional one, the parahippocampal region. We noticed however that the average amplitude of the reference curve obtained from subjects with genetic high-affinity binding for11 C-PBR28 was significantly larger than that from subjects with moderate affinity. This suggests that the reference curve extracted by SVCA was contaminated by specific binding. Conclusion: SVCA allows the noninvasive quantification of inflammatory biomarker translocator protein measured with11 C-PBR28 but without the need of arterial sampling. Although the reference curves were contaminated with specific binding, the decreased variance of the outcome measure, SVCA DVR, allowed for an apparent greater sensitivity to detect regional abnormalities in brains of patients with AD., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2019
- Full Text
- View/download PDF
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