Microglial depletion and activation: A [11C]PBR28 PET study in nonhuman primates.
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ABSTRACT:
SUBMITTER: Hillmer AT
PROVIDER: S-EPMC5524658 | biostudies-other | 2017 Dec
REPOSITORIES: biostudies-other
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Project description:ObjectivesPeripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia and are thereby biomarkers of neuroinflammation. We developed a PET ligand with an aryloxyanilide structure, [O-methyl-(11)C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([(11)C]PBR28), to image PBRs. The objectives of the current study were to evaluate kinetics of brain uptake, and the influence of the peripheral binding on the arterial input function in rhesus monkey.MethodsBrain (baseline: n=6, blocking: n=1) and whole-body PET imaging (baseline: n=3, blocking: n=1) of [(11)C]PBR28 were performed with the measurement of radiometabolite-corrected arterial input function in all brain and two whole body scans.ResultsSaturating doses of nonradioactive PBR ligands markedly increased [(11)C]PBR28 in plasma (approximately 400% increase) and brain (approximately 200%) at 2 min by displacing radioligand from PBRs in peripheral organs. Brain uptake of radioactivity peaked in baseline scans at approximately 40 min after injection of [(11)C]PBR28 and was high (approximately 300% standardized uptake value). The images showed no receptor-free region that could be used for reference tissue analysis. Thus, quantitation of receptor density required measurement of parent radioligand in arterial plasma. Nondisplaceable uptake was estimated from the blocked scans and was only approximately 5% of total distribution volume measured under baseline conditions. Distribution volume of [(11)C]PBR28 was stably determined within 110 min of scanning.ConclusionsRegional brain uptake of [(11)C]PBR28 in monkey could be quantified as a value proportional to the density of receptors--namely, as equilibrium distribution volume. [(11)C]PBR28 had high levels of specific binding in brain and should provide a sensitive measure of changes in PBRs.
| S-EPMC2275117 | biostudies-literature
Project description:DAR-0100A, the active enantiomer of dihydrexidine, is a potent dopamine D1 agonist under investigation for treatment of cognitive impairment and negative symptoms of schizophrenia. We measured the dose-occupancy relationship for DAR-0100A at D1 receptors using positron emission tomography (PET) imaging in baboons with [(11)C] NNC112 and its binding to D2 with [(11)C] raclopride. Two baboons were scanned with [(11)C] NNC112 at baseline and after three different doses of DAR-0100A. Two baboons were scanned with [(11)C] raclopride at baseline and after one dose of DAR-0100A. Occupancy (?BP(ND)) was computed in the striatum and cortex. A clear relationship was observed between plasma concentration of DAR-0100A and ?BP(ND). ?BP(ND) was larger in the striatum than in the cortex, consistent with reports showing that 25% of [(11)C] NNC112 BP(ND) in the cortex is attributed to 5-HT(2A). Plasma EC(50) estimates ranged from 150 to 550 ng/mL according to the constraints on the model. There was no detectable effect of DAR-0100A on [(11)C] raclopride BP(ND). These data suggest that at doses likely to be administered to patients, occupancy will not be detectable with [(11)C] NNC112 PET and binding of DAR-0100A to D2 will be negligible. This is the first demonstration with PET of a significant occupancy by a full D1 agonist in vivo.
| S-EPMC3049493 | biostudies-literature
Project description:We sought to advance methodology for studying microglial activation and putative therapeutic downregulation in response to minocycline by means of noninvasive in vivo imaging. A reproducible focal white matter lesion was used to reliably compare treatment conditions.The corpus callosum of female Sprague Dawley rats was injected with zymosan to promote microglial activation as confirmed by hematoxylin and eosin staining, (3)H-PK11195 autoradiography, and CD11b immunohistochemistry. A subset of subjects was treated systemically with minocycline to potentially alter microglial activation. Seven days after zymosan injection, subjects were imaged with PET using the radiotracer (11)C-(R)-PK11195. In vivo binding was evaluated using the distribution volume ratio (DVR) with respect to a reference region.At the lesion site, the observed (11)C-(R)-PK11195 DVR for each treatment was as follows: mean saline DVR ± SD, 1.17 ± 0.05 (n = 5); zymosan-only DVR, 1.96 ± 0.33 (n = 10); and zymosan with minocycline DVR, 1.58 ± 0.12 (n = 9). Therefore, compared with controls, zymosan increased binding (P = 0.0001, 2-tailed t test) and minocycline treatment reduced zymosan-induced binding by 46% (P = 0.004, 2-tailed t test).Zymosan-induced microglial activation and its response to minocycline can be quantitatively imaged in the rat brain using (11)C-(R)-PK11195 PET. The ability to detect a treatment effect in a focal white-matter lesion may be of use in studying therapies for multiple sclerosis (MS).
| S-EPMC3761794 | biostudies-literature
Project description:The P2X7 receptor plays a significant role in microglial activation, and as a potential drug target, the P2X7 receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X7 receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X7 receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [11C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X7 receptor in vivo in a hP2X7 receptor overexpressing rat model. Although no significant difference in binding of [11C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [11C]SMW139 could be a promising tracer for P2X7 receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X7 receptor overexpressing rat model. However, further investigation of both P2X7 receptor expression and binding of [11C]SMW139 in other neurological diseases involving microglial activation is warranted.
| S-EPMC5920098 | biostudies-literature
Project description:Objective:Postmortem studies reported significant microglia activation in association with neuronal apoptosis in Fatal Familial Insomnia (FFI), indicating a specific glial response, but negative evidence also exists. An in vivo study of local immune responses over FFI natural course may contribute to the understanding of the underlying pathogenesis. Methods:We included eight presymptomatic subjects (mean ± SD age:44.13 ± 3.83 years) carrying the pathogenic D178N-129met FFI mutation, one symptomatic patient (male, 45 yrs. old), and nine healthy controls (HC) (mean ± SD age: 44.00 ± 11.10 years.) for comparisons. 11C-(R)-PK11195 PET allowed the measurement of Translocator Protein (TSPO) overexpression, indexing microglia activation. A clustering algorithm was adopted to define subject-specific reference regions. Voxel-wise statistical analyses were performed on 11C-(R)-PK11195 binding potential (BP) images both at the group and individual level. Results:The D178N-129met/val FFI patient showed significant 11C-(R)-PK11195 BP increases in the midbrain, cerebellum, anterior thalamus, anterior cingulate cortex, orbitofrontal cortex, and anterior insula, bilaterally. Similar TSPO increases, but limited to limbic structures, were observed in four out of eight presymptomatic carriers. The only carrier with the codon 129met/val polymorphism was the only one showing an additional TSPO increase in the anterior thalamus. Interpretation:In comparison to nonprion neurodegenerative diseases, the observed lack of a diffuse brain TSPO overexpression in preclinical and the clinical FFI cases suggests the presence of a different microglia response. The involvement of limbic structures might indicate a role for microglia activation in these key pathologic regions, known to show the most significant neuronal loss and functional deafferentation in FFI.
| S-EPMC5771322 | biostudies-literature
Project description:Recently, we have developed a diphtheria toxin-based recombinant anti-human CCR4 immunotoxin for targeting CCR4+ tumors and Tregs. In this study, we further optimized the dosing schedule for improved CCR4+ Treg depletion. We have demonstrated that up to a 90% depletion was achieved and the depletion extended to approximately 2 weeks in the peripheral blood and more than 48 days in the lymph node at 25 ?g·kg-1 , BID for 8 consecutive days in cynomolgus monkeys. Expansion was observed including monocytes and NK cells. Antibody against the CCR4 immunotoxin was detected after approximately 2 weeks, affecting further depletion efficacy for multiple course treatment.
| S-EPMC6068354 | biostudies-literature
Project description:BackgroundActivated microglia may play a role in the pathogenesis of Alzheimer disease (AD) as they cluster around beta-amyloid (Abeta) plaques. They are, therefore, a potential therapeutic target in both AD and its prodrome amnestic mild cognitive impairment (MCI).ObjectiveTo characterize in vivo with (11)C-(R)-PK11195 and (11)C-PIB PET the distribution of microglial activation and amyloid deposition in patients with amnestic MCI.MethodsFourteen subjects with MCI had (11)C-(R)-PK11195 and (11)C-PIB PET with psychometric tests.ResultsSeven out of 14 (50%) patients with MCI had increased cortical (11)C-PIB retention (p < 0.001) while 5 out of 13 (38%) subjects with MCI showed increased (11)C-(R)-PK11195 uptake. The MCI subgroup with increased (11)C-PIB retention also showed increased cortical (11)C-(R)-PK11195 binding (p < 0.036) though this increase only remained significant in frontal cortex after a correction for multiple comparisons. There was no correlation between regional levels of (11)C-(R)-PK11195 and (11)C-PIB binding in individual patients with MCI: only three of the five MCI cases with increased (11)C-(R)-PK11195 binding had increased levels of (11)C-PIB retention.ConclusionsOur findings indicate that, while amyloid deposition and microglial activation can be detected in vivo in around 50% of patients with mild cognitive impairment (MCI), these pathologies can occur independently. The detection of microglial activation in patients with MCI suggests that anti-inflammatory therapies may be relevant to the prevention of AD.
| S-EPMC2817573 | biostudies-literature
Project description:Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [(11)C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [(18)F]DOPP ([(18)F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising (18)F-labeled analogue based on rodent studies. The goal of this work is to evaluate [(18)F]DOPP in nonhuman primates to support its clinical translation. High specific activity [(18)F]DOPP (5-6 Ci·?mol(-1)) was administered intravenously (iv) to three baboons (2M/1F, 3-4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 ?g/kg iv, 10 min prior to [(18)F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ?95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [(18)F]DOPP covalently links to the active site of FAAH. Consistent with previous findings for [(11)C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter ?k3 was therefore used to evaluate whole brain (WB) and regional binding of [(18)F]DOPP. Pretreatment studies showed inhibition of ?k3 across all brain regions (WB baseline: 0.112 mL/cm(3)/min; 300 ?g/kg URB597: 0.058 mL/cm(3)/min), suggesting that [(18)F]DOPP binding is specific for FAAH, consistent with previous rodent data.
| S-EPMC4224570 | biostudies-literature
Project description:Many features of T-cell homeostasis in primates are still unclear, thus limiting our understanding of AIDS pathogenesis, in which T-cell homeostasis is lost. Here, we performed experiments of in vivo CD4(+) or CD8(+) lymphocyte depletion in 2 nonhuman primate species, rhesus macaques (RMs) and sooty mangabeys (SMs). Whereas RMs develop AIDS after infection with simian immunodeficiency virus (SIV), SIV-infected SMs are typically AIDS-resistant. We found that, in both species, most CD4(+) or CD8(+) T cells in blood and lymph nodes were depleted after treatment with their respective antibodies. These CD4(+) and CD8(+) lymphocyte depletions were followed by a largely lineage-specific CD4(+) and CD8(+) T-cell proliferation, involving mainly memory T cells, which correlated with interleukin-7 plasma levels. Interestingly, SMs showed a faster repopulation of naive CD4(+) T cells than RMs. In addition, in both species CD8(+) T-cell repopulation was faster than that of CD4(+) T cells, with CD8(+) T cells reconstituting a normal pool within 60 days and CD4(+) T cells remaining below baseline levels up to day 180 after depletion. While this study revealed subtle differences in CD4(+) T-cell repopulation in an AIDS-sensitive versus an AIDS-resistant species, such differences may have particular relevance in the presence of active SIV repli cation, where CD4(+) T-cell destruction is chronic.
| S-EPMC2918331 | biostudies-other
Project description:In addition to extracellular ?-amyloid plaques and intracellular neurofibrillary tangles, neuroinflammation has been identified as a key pathological characteristic of Alzheimer's disease (AD). Once activated, neuroinflammatory cells called microglia acquire different activation phenotypes. At the early stage of AD, activated microglia are mainly dominated by the neuroprotective and anti-inflammatory M2 phenotype. Conversely, in the later stage of AD, the excessive activation of microglia is considered detrimental and pro-inflammatory, turning into the M1 phenotype. Therapeutic strategies targeting the modulation of microglia may regulate their specific phenotype. Fortunately, with the rapid development of in vivo imaging methodologies, visualization of microglial activation has been well-explored. In this review, we summarize the critical role of activated microglia during the pathogenesis of AD and current studies concerning imaging of microglial activation in AD patients. We explore the possibilities for identifying activated microglial phenotypes with imaging techniques and highlight promising therapies that regulate the microglial phenotype in AD mice.
| S-EPMC6186779 | biostudies-other