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In this study, lactoferrin-conjugated PEGylated liposomes (PL), a potential drug carrier for brain delivery, was loaded with radioisotope complex, 99mTc labeled N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (99mTc-BMEDA) for in vitro and in vivo evaluations. The hydrophilicity of liposomes was enhanced by PEGylation which was not an ideal brain delivery system for crossing the blood brain barrier (BBB). With the modification of a brain-targeting ligand, lactoferrin (Lf), the PEGylated liposome (PL) might become a potential brain delivery vehicle. In order to test the hypothesis in vitro and in vivo, 99mTc-BMEDA was loaded into the liposomes as a reporter with or without Lf-conjugation. The mouse brain endothelia cell line, bEnd.3 cells, was cultured to investigate the potential uptake of liposomes in vitro. The in vivo uptake by the mouse brain of the liposomes was detected by tissue biodistribution study. The results indicated that Lf-conjugated PEGylated liposome showed more than three times better uptake efficiency in vitro and two-fold higher of brain uptake in vivo than PEGlyated liposome. With the success of loading the potential Single Photon Emission Tomography (SPECT) imaging probe, 99mTc-BMEDA, Lf-PL might serve as a promising brain delivery system for loading diagnostics or therapeutics of various brain disorders.

Many secretory tissues release Zn(II) ions along with other molecules in response to external stimuli. Here we demonstrate that secretion of Zn(II) ions from normal, healthy prostate tissue is stimulated by glucose in fasted mice and that release of Zn(II) can be monitored by MRI. An ∼50% increase in water proton signal enhancement is observed in T₁-weighted images of the healthy mouse prostate after infusion of a Gd-based Zn(II) sensor and an i.p. bolus of glucose. Release of Zn(II) from intracellular stores was validated in human epithelial prostate cells in vitro and in surgically exposed prostate tissue in vivo using a Zn(II)-sensitive fluorescent probe known to bind to the extracellular surface of cells. Given the known differences in intracellular Zn(II) stores in healthy versus malignant prostate tissues, the Zn(II) sensor was then evaluated in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model in vivo. The agent proved successful in detecting small malignant lesions as early as 11 wk of age, making this noninvasive MR imaging method potentially useful for identifying prostate cancer in situations where it may be difficult to detect using current multiparametric MRI protocols.

Purpose Colony-stimulating factor 1 receptor (CSF1R) signaling plays a pivotal role in neuroinflammation, driving microglia proliferation and activation. CSF1R is considered a hallmark of inflammation in many neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Our study aims to evaluate the potential value of 5-cyano-N-(4-(4-(2-([ 18 F]fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([ 18 F]JNJ-CSF1R-1) as a positron emission tomography (PET) ligand targeting CSF1R in preclinical models of neuroinflammation. Procedures A cell-based MSD assay was used to measure the IC 50 of 5-cyano-N-(4-(4-(2-(fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (JNJ-CSF1R-1). JNJ-CSF1R-1 was radiolabeled with fluorine-18. PET imaging was used to evaluate brain uptake, and target engagement of [ 18 F]JNJ-CSF1R-1 in two neuroinflammation mouse models, including systemic lipopolysaccharide (LPS) and App SAA knock in (KI). CSF1R protein levels in brain tissue were determined by western blot and ELISA assays. [ 18 F]JNJ-CSF1R-1 brain uptake was also measured in a non-human primate (NHP) PET study. Results JNJ-CSF1R-1 is a 12 nM (IC 50 ) inhibitor of CSF1R. ​[ 18 F]JNJ-CSF1R-1 demonstrated significantly higher brain uptake in both LPS and AD mouse models as measured by the area under the time activity curves (AUC) compared to control animals. In the App SAA KI model, CSF1R levels increased near amyloid plaques as detected by IHC. ​[ 18 F]JNJ-CSF1R-1 PET imaging signal showed a good correlation with CSF1R expression levels measured by western blot and ELISA. In an NHP study, ​[ 18 F]JNJ-CSF1R-1 readily entered the brain and demonstrated reversible kinetics. Conclusion ​[ 18 F]JNJ-CSF1R-1 is a potent and promising CSF1R PET tracer with translational potential for measuring microglia-based neuroinflammatory processes and for tracking the impact of anti-inflammatory therapies.

Colony-stimulating factor 1 receptor (CSF1R) signaling plays a pivotal role in neuroinflammation, driving microglia proliferation and activation. CSF1R is considered a hallmark of inflammation in many neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Our study aims to evaluate the potential value of 5-cyano-N-(4-(4-(2-([18F]fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([18F]JNJ-CSF1R-1) as a positron emission tomography (PET) ligand targeting CSF1R in preclinical models of neuroinflammation.PURPOSEColony-stimulating factor 1 receptor (CSF1R) signaling plays a pivotal role in neuroinflammation, driving microglia proliferation and activation. CSF1R is considered a hallmark of inflammation in many neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Our study aims to evaluate the potential value of 5-cyano-N-(4-(4-(2-([18F]fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([18F]JNJ-CSF1R-1) as a positron emission tomography (PET) ligand targeting CSF1R in preclinical models of neuroinflammation.A cell-based MSD assay was used to measure the IC50 of 5-cyano-N-(4-(4-(2-(fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (JNJ-CSF1R-1). JNJ-CSF1R-1 was radiolabeled with fluorine-18. PET imaging was used to evaluate brain uptake, and target engagement of [18F]JNJ-CSF1R-1 in two neuroinflammation mouse models, including systemic lipopolysaccharide (LPS) and AppSAA knock in (KI). CSF1R protein levels in brain tissue were determined by western blot and ELISA assays. [18F]JNJ-CSF1R-1 brain uptake was also measured in a non-human primate (NHP) PET study.PROCEDURESA cell-based MSD assay was used to measure the IC50 of 5-cyano-N-(4-(4-(2-(fluoro)ethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (JNJ-CSF1R-1). JNJ-CSF1R-1 was radiolabeled with fluorine-18. PET imaging was used to evaluate brain uptake, and target engagement of [18F]JNJ-CSF1R-1 in two neuroinflammation mouse models, including systemic lipopolysaccharide (LPS) and AppSAA knock in (KI). CSF1R protein levels in brain tissue were determined by western blot and ELISA assays. [18F]JNJ-CSF1R-1 brain uptake was also measured in a non-human primate (NHP) PET study.JNJ-CSF1R-1 is a 12 nM (IC50) inhibitor of CSF1R. ​[18F]JNJ-CSF1R-1 demonstrated significantly higher brain uptake in both LPS and AD mouse models as measured by the area under the time activity curves (AUC) compared to control animals. In the AppSAA KI model, CSF1R levels increased near amyloid plaques as detected by IHC. ​[18F]JNJ-CSF1R-1 PET imaging signal showed a good correlation with CSF1R expression levels measured by western blot and ELISA. In an NHP study, ​[18F]JNJ-CSF1R-1 readily entered the brain and demonstrated reversible kinetics.RESULTSJNJ-CSF1R-1 is a 12 nM (IC50) inhibitor of CSF1R. ​[18F]JNJ-CSF1R-1 demonstrated significantly higher brain uptake in both LPS and AD mouse models as measured by the area under the time activity curves (AUC) compared to control animals. In the AppSAA KI model, CSF1R levels increased near amyloid plaques as detected by IHC. ​[18F]JNJ-CSF1R-1 PET imaging signal showed a good correlation with CSF1R expression levels measured by western blot and ELISA. In an NHP study, ​[18F]JNJ-CSF1R-1 readily entered the brain and demonstrated reversible kinetics.​[18F]JNJ-CSF1R-1 is a potent and promising CSF1R PET tracer with translational potential for measuring microglia-based neuroinflammatory processes and for tracking the impact of anti-inflammatory therapies.CONCLUSION​[18F]JNJ-CSF1R-1 is a potent and promising CSF1R PET tracer with translational potential for measuring microglia-based neuroinflammatory processes and for tracking the impact of anti-inflammatory therapies.

Aromatase synthesizes estrogens from androgens. While the gonads are major sites of aromatase expression, it is expressed in multiple other organs including adipose tissue, brain and bone. In global aromatase knockouts in mice, studied by us, or man aromatase deficiency there are phenotypes of adiposity and low bone mass as well as varying degrees of insulin resistance. Breast cancer patients treated with aromatase inhibitors (AIs) also develop adiposity and low bone mass. Thus, it remains unclear the role of site specific aromatase activity in the phenotypes observed in chemically or genetically induced aromatase deficiency. To begin to understand the relative contributions of tissue specific aromatase activity and develop a model that will be useful for understanding and developing therapeutic strategies for ailments in aromatase inhibitor therapy, we have developed mouse models with tissue specific aromatase inactivation. Embryonic stem cells were purchased from EUCOMM. Using standard methods and appropriate breeding strategies we generated C57Bl6 mice with Lox P sites flanking Exon 2 in the aromatase gene (Arom fl/fl). Mice with adipose specific inactivation of aromatase were generated by interbreeding Arom fl/fl mice with mice expressing Cre recombinase driven by the adiponectin promoter (AdipoCre). We measured body composition by dual energy x-ray absorptiometry (Lunar PIXIMus 2). As a first step in examining glucose homeostasis we performed oral glucose tolerance tests. All mice were fed normal chow and the study was approved by the local IACUC. Female mice aged 4-6 months were studied with at least 4 animals in each group. Arom fl/fl mice were compared as controls for the AdipoCre+; Arom fl/fl mice. Mean body weight was higher in fat specific aromatase knockout female mice (33.6 vs 21.6, p<0.05). On DEXA Mean %Body fat was higher in female AdipoCre+;Arom fl/fl mice (29.3% vs. 17.3%, p<0.05). Following a 16h fast female mice with adipose specific aromatase inactivation had higher fasting blood glucose levels (93.3+/-10.3 vs 74.5+/-10, p=0.03). For the glucose tolerance test, a bolus of glucose (2 g/kg) was delivered into the stomach by a gavage needleand blood was sampled at 0, 5, 10, 20, 30, 60, 90, 120, and 180 min for plasma glucose analyses. On OGTT peak glucose levels were higher and did not return to baseline. Insulin tolerance tests will be performed to further understand the mechanism of impaired glucose homeostasis. Male mice with fat specific aromatase inactivation showed similar patterns in higher body weight, percent body fat and glucose levels but the phenotype was more variable. In summary, fat specific aromatase inactivation is sufficient to cause adiposity and impaired glucose homeostasis. The observed phenotype in females is more robust than we have observed in the global knockout.

Aim： Ferulic acid （4-hydroxy-3-methoxycinnamic acid, FA） provides neuroprotection against apoptosis in a transient middle cerebral artery occlusion （MCAo） model. This study was to further investigate the anti-apoptotic effect of FA during reperfusion after cerebral ischemia. Methods： Rats were subjected to 90 min of cerebral ischemia followed by 3 or 24 h of reperfusion after which they were sacrificed. Results： Intravenous FA （100 mg/kg） administered immediately after middle cerebral artery occlusion （MCAo） or 2 h after reperfusion effectively abrogated the elevation of postsynaptic density-95 （PSD-95）, neuronal nitric oxide synthase （nNOS）, inducible nitric oxide synthase （iNOS）, nitrotyrosine, and cleaved caspase-3 levels as well as apoptosis in the ischemic cortex at 24 h of reperfusion. FA fur- ther inhibited Bax translocation, cytochrome c release, and p38 mitogen-activated protein （MAP） kinase phosphorylation. Moreover, FA enhanced the expression of gamma-aminobutyric acid type B receptor subunit 1 （GABAB1） in the ischemic cortex at 3 and 24 h of reperfusion. In addition, nitrotyrosine-positive cells colocalized with cleaved caspase-3-positive cells, and phospho-p38 MAP kinase- positive cells cotocalized with nitrotyrosine- and Bax-positive cells, indicating a positive relationship among the expression of nitroty- rosine, phospho-p38 MAP kinase, Bax, and cleaved caspase-3. The mutually exclusive expression of GABA81and nitrotyrosine revealed that there is a negative correlation between GABAB1 and nitrotyrosine expression profiles. Additionally, pretreatment with saclofen, a GABAe receptor antagonist, abolished the neuroprotection of FA against nitric oxide （NO）-induced apoptosis. Conclusion： FA significantly enhances GABAB1 receptor expression at early reperfusion and thereby provides neuroprotection against p38 MAP kinase-mediated NO-induced apoptosis at 24 h of reperfusion.