Publications by authors named "Meri De Angelis"

37 Publications

Multiple persistent organic pollutants in mothers' breastmilk: Implications for infant dietary exposure and maternal thyroid hormone homeostasis in Uganda, East Africa.

Sci Total Environ 2021 May 20;770:145262. Epub 2021 Jan 20.

Department of Chemistry, Makerere University, P. O. Box 7062, Kampala, Uganda. Electronic address:

Persistent organic pollutants (POPs) are ubiquitous contaminants with adverse health effects in the ecosystem. One of such effects is endocrine disruption in humans and wildlife even at background exposure concentrations. This study assessed maternal breastmilk concentrations of POPs; brominated flame retardants (BFRs), polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs), and the potential health risks posed to the nursing infants. We also evaluated the association of these POPs with total 3,3',5-triiodo-L-thyronine (T), L-thyroxine (T), and 3,3',5'-triiodo-L-thyronine (rT) levels measured in human breast milk. Thirty breastmilk samples were collected from Kampala, Uganda between August and December 2018. Hexabromobenzene was not detected while the maximum level of 2,2',4,4',5,5'-hexabrombiphenyl was 64.7 pg/g lw. The median levels of total indicator PCBs, PBDEs, dioxin-like PCBs, and PCDD/Fs in the samples were 159 pg/g lw, 511 pg/g lw, 1.16 pg TEQ/g lw, and 0.4 pg TEQ/g lw, respectively. These levels were lower than those reported in other countries. Owing to their bio accumulative nature, PCBs -81, -169, and ∑PCDD/Fs increased with increase in maternal age. Estimated dietary intakes for dioxin-like PCBs and PCDD/Fs were lower than those reported elsewhere but were higher than the WHO tolerable daily intakes suggesting potential health risks to nursing infants. In adjusted single pollutant models, PCB-126, PCB-169, and ∑PCB were negatively associated with T, while 1,2,3,4,5,7,8-HpCDF was positively associated with rT. Although these associations did not persist in multipollutant models, our findings suggest potential thyroid hormone disruption by POPs in mothers. This may reduce the levels of thyroid hormones transferred from the mother to the neonates and, hence, adversely influence infant growth. A temporal study with a bigger sample size is required to corroborate these findings.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145262DOI Listing
May 2021

Determination of 3-iodothyronamine (3-TAM) in mouse liver using liquid chromatography-tandem mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Feb 18;1165:122553. Epub 2021 Jan 18.

Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Molecular EXposomics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.

3-iodothyronamine (3-TAM) has been suggested as a novel chemical messenger and potent trace amine-associated receptor 1 ligand in the CNS that occurs naturally as endogenous metabolite of the thyroid hormones. Discrepancies and variations in 3-TAM plasma and tissue concentrations have nonetheless caused controversy regarding the existence and biological role of 3-TAM. These discussions are at least partially based on potential analytical artefacts caused by differential decay kinetics of 3-TAM and the widely used deuterated quantification standard D-TAM. Here, we report a novel LC-MS/MS method for the quantification of 3-TAM in biological specimens using stable isotope dilution with C-TAM, a new internal standard that showed pharmacodynamic properties comparable to endogenous 3-TAM. The method detection limit (MDL) and method quantification limit (MQL) of 3-TAM were 0.04 and 0.09 ng/g, respectively. The spike-recoveries of 3-TAM were between 85.4% and 94.3%, with a coefficient of variation of 3.7-5.8%. The intra-day and inter-day variations of 3-TAM were 8.45-11.2% and 3.58-5.73%, respectively. Endogenous 3-TAM liver values in C57BL/6J mice were 2.20 ± 0.49 pmol/g with a detection frequency of 50%. Higher liver 3-TAM values were found when C57BL/6J mice were treated with N-acetyl-3-iodothyronamine or O-acetyl-3-iodothyronamine. Overall, our new stable isotope dilution LC-MS/MS method improves both the sensitivity and selectivity compared with existing methods. The concomitant possibility to quantify additional thyroid hormones such as thyroxine, 3,5,3'-triiodo--thyronine, 3,3',5'-triiodo--thyronine, 3,3'-diiodo--thyronine, and 3,5-diiodo--thyronine further adds to the value of our novel method in exploring the natural occurrence and fate of 3-TAM in biological tissues and fluids.
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http://dx.doi.org/10.1016/j.jchromb.2021.122553DOI Listing
February 2021

Placental distribution of endogenous and exogenous substances: A pilot study utilizing cryo-sampled specimen off delivery room.

Placenta 2020 10 11;100:45-53. Epub 2020 Aug 11.

Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Molecular EXposomics, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany. Electronic address:

Introduction: Reliability in the use of placentome (including placenta, umbilical cord, and cord blood) biomarkers requires an understanding of their distributions. Here we aim to develop a simple and proper placenta sampling scheme, and to evaluate the placental distributions of biomarkers.

Methods: We developed a continuous cooling chain protocol off delivery room and cryo-subsampling method for placenta sampling. The levels of thyroid hormones (THs), elements, persistent organic pollutants (POPs), monoamines, and vitamin E were measured using UPLC-Q-TOF-MS, HPLC-ICP-MS, HPLC-EcD, and HRGC-HRMS, respectively. The distributions of biomarkers were assessed.

Results: In human placentome, -thyroxine (T), Cd, Se, Zn, Cu, Fe, Ca, K, Mg, α-tocopherol, β-tocopherol, and β-tocotrienol levels were higher in placenta than in umbilical cord, while Pb and Mn were concentrated in human cord. In porcine placentome, T, 3,3',5'-triiodo--thyronine (rT), 3,3'-diiodo--thyronine, Cd, Pb, Zn, K, and Al levels were higher in the cord. The intraclass correlation coefficient (ICC) was <0.4 for 3,3',5-triiodo--thyronine, rT, α-tocopherol, and 7 elements in human basal plate, indicating low reliability. rT, Cd, Zn, Mn, and Cu were significantly concentrated in the central region in human placenta, while higher levels of As, Cd, Cr, and Al were found in the periphery region in porcine placenta. Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) showed moderate reliability (ICC: 0.40-0.98) except PCB-81, -126, and BDE-208, while polychlorinated dibenzo-p-doixins/furans (PCDD/Fs) showed poor reliability (ICC: 0.07-0.31).

Discussion: These results highlight the complexity of placenta sampling. This study provides a novel and simple sampling approach in investigating placental exposomics.
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http://dx.doi.org/10.1016/j.placenta.2020.08.009DOI Listing
October 2020

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.

J Clin Invest 2020 11;130(11):6093-6108

Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany.

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.
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http://dx.doi.org/10.1172/JCI136363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598066PMC
November 2020

Detection and quantification of the anti-obesity drug celastrol in murine liver and brain.

Neurochem Int 2020 06 6;136:104713. Epub 2020 Mar 6.

Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Research Unit Neurobiology of Diabetes, 85764, Neuherberg, Germany; Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Institute for Diabetes and Obesity, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany; Technical University of Munich, Neurobiology of Diabetes, TUM School of Medicine, 81675, Munich, Germany. Electronic address:

Celastrol is a natural pentacyclic triterpene extracted from the roots of Tripterygium wilfordi (thunder god vine). Celastrol was reported as a powerful anti-obesity drug with leptin sensitizing properties that decreases food consumption and mediates body weight loss when administered to diet-induced obese mice at 100 μg/kg body weight. The weight lowering properties of celastrol are likely mediated by the CNS, in particular, by the hypothalamus, but the final proof for the accumulation of celastrol in the brain and hypothalamus remains to be established. Here, we aimed to demonstrate that intraperitoneal celastrol administration at 100 μg/kg can rapidly reach the brain and, in particular, the hypothalamus of mice. We developed and validated a sensitive liquid chromatography mass spectrometry method for the quantitative determination of celastrol in murine tissues, namely liver, brain and hypothalamus. Chow-fed lean mice were randomly assigned to the vehicle vs. celastrol groups, injected with saline or 100 μg/kg body weight of celastrol, and sacrificed 30 min or 120 min post injection. Celastrol was extracted from homogenized tissue using ethyl acetate as organic solvent, and quantified using a matrix-matched calibration curve with glycyrrhetinic acid as internal standard. Liver celastrol concentrations were 32.60 ± 8.21 pg/mg and 40.52 ± 15.6 pg/mg, 30 and 120 min after injection, respectively. We found 4.70 ± 0.31 pg/mg celastrol after 30 min, and 16.22 ± 3.33 pg/mg after 120 min in whole brain lysates, and detectable amounts in the hypothalamus. These results corroborate the validity of our methodology, demonstrate the accumulation of celastrol in the brain of mice injected intraperitoneally with a dose of 100 μg/kg, and confirm the CNS as possible site of action for the weight lowering properties of celastrol.
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http://dx.doi.org/10.1016/j.neuint.2020.104713DOI Listing
June 2020

Pharmacological targeting of α3β4 nicotinic receptors improves peripheral insulin sensitivity in mice with diet-induced obesity.

Diabetologia 2020 06 6;63(6):1236-1247. Epub 2020 Mar 6.

Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.

Aims/hypothesis: Treatment with the α3β4 nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), improves glucose tolerance in diet-induced obese (DIO) mice, but the physiological and molecular mechanisms are unknown.

Methods: DMPP (10 mg/kg body weight, s.c.) was administered either in a single injection (acute) or daily for up to 14 days (chronic) in DIO wild-type (WT) and Chrnb4 knockout (KO) mice and glucose tolerance, tissue-specific tracer-based glucose metabolism, and insulin signalling were assessed.

Results: In WT mice, but not in Chrnb4 KO mice, single acute treatment with DMPP induced transient hyperglycaemia, which was accompanied by high plasma adrenaline (epinephrine) levels, upregulated hepatic gluconeogenic genes, and decreased hepatic glycogen content. In contrast to these acute effects, chronic DMPP treatment in WT mice elicited improvements in glucose tolerance already evident after three consecutive days of DMPP treatment. After seven days of DMPP treatment, glucose tolerance was markedly improved, also in comparison with mice that were pair-fed to DMPP-treated mice. The glycaemic benefit of chronic DMPP was absent in Chrnb4 KO mice. Chronic DMPP increased insulin-stimulated glucose clearance into brown adipose tissue (+69%), heart (+93%), gastrocnemius muscle (+74%) and quadriceps muscle (+59%), with no effect in white adipose tissues. After chronic DMPP treatment, plasma adrenaline levels did not increase following an injection with DMPP. In glucose-stimulated skeletal muscle, we detected a decreased phosphorylation of the inhibitory Ser640 phosphorylation site on glycogen synthase and a congruent increase in glycogen accumulation following chronic DMPP treatment.

Conclusions/interpretation: Our data suggest that DMPP acutely induces adrenaline release and hepatic glycogenolysis, while chronic DMPP-mediated activation of β4-containing nAChRs improves peripheral insulin sensitivity independently of changes in body weight via mechanisms that could involve increased non-oxidative glucose disposal into skeletal muscle.
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http://dx.doi.org/10.1007/s00125-020-05117-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228898PMC
June 2020

Persistent Organic Pollutants in Human Breast Milk and Associations with Maternal Thyroid Hormone Homeostasis.

Environ Sci Technol 2020 01 9;54(2):1111-1119. Epub 2020 Jan 9.

Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Molecular EXposomics , Ingolstädter Landstr. 1 , 85764 Neuherberg , Germany.

Epidemiological studies have indicated the thyroid-disrupting effects of persistent organic pollutants (POPs). However, the association of low-exposure POPs with thyroid hormones (THs) remains unclear. Here, we aim to assess the association of low exposure of POPs, including polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polychlorinated dibenzo--dioxins and furans (PCDD/Fs), and polybrominated dibenzo--dioxins and furans, with THs [total -thyroxine (TT), total 3,3',5-triiodo--thyronine (TT), and total 3,3',5'-triiodo--thyronine (TrT)] measured in human breast milk. Ninety-nine breast milk samples were collected from the LUPE cohort (2015-2016, Bavaria, Germany). Fourteen PBDEs, 17 PCBs, and 5 PCDD/Fs had quantification rates of >80%. Nonmonotonic associations were observed. In adjusted single-pollutant models, (1) TT was inversely associated with BDE-99, -154, and -196; (2) TT was inversely associated with BDE-47, -99, -100, -197, -203, -207, and OCDD; and (3) TrT was inversely associated with BDE-47, -99, -183, and -203. Multipollutant analysis using principal component analysis and hierarchical clustering revealed inverse associations of PBDEs (BDE-28, -47, -99, -100, -154, -183, and -197) with TT and TrT. These results indicate that POPs at low levels might be related to reduced THs. This study shows that human breast milk might be an appropriate specimen to evaluate the thyroid disruption of POPs.
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http://dx.doi.org/10.1021/acs.est.9b06054DOI Listing
January 2020

Aging Is Associated with Low Thyroid State and Organ-Specific Sensitivity to Thyroxine.

Thyroid 2019 12 26;29(12):1723-1733. Epub 2019 Sep 26.

Department of Endocrinology, Diabetes and Metabolism; Department of Endocrinology, Diabetes and Metabolism; University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Serum thyroid state in older adults correlates with extended longevity. We hypothesized that age impacts not only systemic but also organ-specific thyroid state and response to thyroxine (T4). Young (3 months) and old (23 months) male mice were analyzed at baseline and after acute T4 challenge. Age effects on circulating thyrotropin (TSH) and thyroid hormone (TH) concentrations, transcript expression in the pituitary and thyroid were compared with organ-specific responses characterized by hepatic and cardiac content of TH and TH metabolites and expression of TH-target genes, as well as hepatic deiodinase 1 activity. Circulating TH concentrations and hepatic and cardiac TH content were lower in old versus young mice. After injection with T4, conversion of T4 to triiodothyronine was decreased in old mice while TH transport in liver and heart was not affected. Organ-specific TH response was augmented in old mice in liver but not heart, indicating age- and tissue-specific sensitivity to TH. A compensatory increase of expression in the pituitary and increased serum TSH concentrations, but reduced expression of thyroid differentiation markers were found in old mice. We suggest that a reduced activity of the aged thyroid is responsible for the systemic low TH state in old mice. Further, divergent TH metabolism and tissue response in liver and heart occur after T4 treatment in an aged organism. These rodent data are in agreement with a much narrower window for T4 substitution in the older adults to avoid overtreatment.
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http://dx.doi.org/10.1089/thy.2018.0377DOI Listing
December 2019

Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus.

J Med Chem 2018 12 7;61(24):11144-11157. Epub 2018 Dec 7.

Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.

Celastrol is a natural pentacyclic triterpene used in traditional Chinese medicine with significant weight-lowering effects. Celastrol-administered mice at 100 μg/kg decrease food consumption and body weight via a leptin-dependent mechanism, yet its molecular targets in this pathway remain elusive. Here, we demonstrate in vivo that celastrol-induced weight loss is largely mediated by the inhibition of leptin negative regulators protein tyrosine phosphatase (PTP) 1B (PTP1B) and T-cell PTP (TCPTP) in the arcuate nucleus (ARC) of the hypothalamus. We show in vitro that celastrol binds reversibly and inhibits noncompetitively PTP1B and TCPTP. NMR data map the binding site to an allosteric site in the catalytic domain that is in proximity of the active site. By using a panel of PTPs implicated in hypothalamic leptin signaling, we show that celastrol additionally inhibited PTEN and SHP2 but had no activity toward other phosphatases of the PTP family. These results suggest that PTP1B and TCPTP in the ARC are essential for celastrol's weight lowering effects in adult obese mice.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01224DOI Listing
December 2018

Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1.

Diabetes 2018 11 28;67(11):2456-2465. Epub 2018 Aug 28.

Research Unit Neurobiology of Diabetes, Helmholtz Zentrum München, Neuherberg, Germany

Celastrol, a plant-derived constituent of traditional Chinese medicine, has been proposed to offer significant potential as an antiobesity drug. However, the molecular mechanism for this activity is unknown. We show that the weight-lowering effects of celastrol are driven by decreased food consumption. Although young Lep mice respond with a decrease in food intake and body weight, adult Lep and Lep mice are unresponsive to celastrol, suggesting that functional leptin signaling in adult mice is required to elicit celastrol's catabolic actions. Protein tyrosine phosphatase 1 (PTP1B), a leptin negative-feedback regulator, has been previously reported to be one of celastrol's targets. However, we found that global PTP1B knockout (KO) and wild-type (WT) mice have comparable weight loss and hypophagia when treated with celastrol. Increased levels of uncoupling protein 1 (UCP1) in subcutaneous white and brown adipose tissue suggest celastrol-induced thermogenesis as a further mechanism. However, diet-induced obese UCP1 WT and KO mice have comparable weight loss upon celastrol treatment, and celastrol treatment has no effect on energy expenditure under ambient housing or thermoneutral conditions. Overall, our results suggest that celastrol-induced weight loss is hypophagia driven and age-dependently mediated by functional leptin signaling. Our data encourage reconsideration of therapeutic antiobesity strategies built on leptin sensitization.
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http://dx.doi.org/10.2337/db18-0146DOI Listing
November 2018

Association of In Utero Persistent Organic Pollutant Exposure With Placental Thyroid Hormones.

Endocrinology 2018 10;159(10):3473-3481

Helmholtz Zentrum München-German Research Center for Environmental Health, Molecular EXposomics, Neuherberg, Germany.

In utero exposure to persistent organic pollutants (POPs) can result in thyroid function disorder, leading to concerns about their impact on fetal and neonatal development. The associations between placental levels of various POPs and thyroid hormones (THs) were investigated. In a prospective Danish study initially established for assessing congenital cryptorchidism, 58 placenta samples were collected from mothers of boys born with (n = 28) and without (n = 30) cryptorchidism. The concentrations of polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs), organotin chemicals (OTCs), organochlorine pesticides (OCPs), T4, T3, and rT3 were measured. The associations between placental THs and various POPs were analyzed using multiple linear regression. Five PBDEs, 35 PCBs, 14 PCDD/Fs, 3 OTCs, 25 OCPs, T4, T3, and rT3 were measured. No correlation between THs and the odds of cryptorchidism was found. Several POPs were significantly associated with THs: (1) T4 was inversely associated with BDEs 99, 100, ΣPBDE, and 2378-TeCDD, and positively associated with 1234678-HpCDF; (2) T3 was positively associated with 2378-TeCDF and 12378-PeCDF; and (3) rT3 was positively associated with PCB 81, 12378-PeCDF, and 234678-HxCDF, and inversely associated with tributyltin, ΣOTC, and methoxychlor. These results revealed that POP exposures were associated with TH levels in placenta, which may be a possible mechanism for the impacts of POP exposures on children's growth and development. This study provides new insight into the complexity of thyroid-disrupting properties of POPs. More research is needed to elucidate the biological consequences of POP exposures.
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http://dx.doi.org/10.1210/en.2018-00542DOI Listing
October 2018

Determination of thyroid hormones in placenta using isotope-dilution liquid chromatography quadrupole time-of-flight mass spectrometry.

J Chromatogr A 2018 Jan 24;1534:85-92. Epub 2017 Dec 24.

Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Molecular EXposomics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.

The transplacental passage of thyroid hormones (THs) is of great significance since the maternal THs are vitally important in ensuring the normal fetal development. In this paper, we determined the concentrations of seven THs, viz. L-thyroxine (T), 3,3',5-triiodo-l-thyronine (T), 3,3',5'-triiodo-l-thyronine (rT), 3,3'-diiodo-l-thyronine (T), 3,5-diiodo-l-thyronine (rT), 3-iodo-l-thyronine (T) and 3-iodothyronamine (TAM), in placenta using isotope dilution liquid chromatography quadrupole time-of-flight mass spectrometry. We optimized the method using isotopically labeled quantification standards (C-T, C-T, C-rT and C-T) and recovery standard (C-T) in combination with solid-liquid extraction, liquid-liquid extraction and solid phase extraction. The linearity was obtained in the range of 0.5-150 pg uL with R values >0.99. The method detection limits (MDLs) ranged from 0.01 ng g to 0.2 ng g, while the method quantification limits (MQLs) were between 0.04 ng g and 0.7 ng g. The spike-recoveries for THs (except for T and TAM) were in the range of 81.0%-112%, with a coefficient of variation (CV) of 0.5-6.2%. The intra-day CVs and inter-day CVs were 0.5%-10.3% and 1.19%-8.88%, respectively. Concentrations of the THs were 22.9-35.0 ng g T, 0.32-0.46 ng g T, 2.86-3.69 ng g rT, 0.16-0.26 ng g T, and < MDL for other THs in five human placentas, and 2.05-3.51 ng g T, 0.37-0.62 ng g T, 0.96-1.3 ng g rT, 0.07-0.13 ng g T and < MDL for other THs in five mouse placentas. The presence of T was tracked in placenta for the first time. This method with improved selectivity and sensitivity allows comprehensive evaluation of TH homeostasis in research of metabolism and effects of environmental contaminant exposures.
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http://dx.doi.org/10.1016/j.chroma.2017.12.048DOI Listing
January 2018

Comprehensive analysis of nine monoamines and metabolites in small amounts of peripheral murine (C57Bl/6 J) tissues.

Biomed Chromatogr 2018 Apr 12;32(4). Epub 2017 Dec 12.

Helmholtz Center Munich-German Research Center for Environmental Health, Molecular EXposomics, Neuherberg, Germany.

Monoamines, acting as hormones and neurotransmitters, play a critical role in multiple physiological processes ranging from cognitive function and mood to sympathetic nervous system activity, fight-or-flight response and glucose homeostasis. In addition to brain and blood, monoamines are abundant in several tissues, and dysfunction in their synthesis or signaling is associated with various pathological conditions. It was our goal to develop a method to detect these compounds in peripheral murine tissues. In this study, we employed a high-performance liquid chromatography method using electrochemical detection that allows not only detection of catecholamines but also a detailed analysis of nine monoamines and metabolites in murine tissues. Simple tissue extraction procedures were optimized for muscle (gastrocnemius, extensor digitorum longus and soleus), liver, pancreas and white adipose tissue in the range of weight 10-200 mg. The system allowed a limit of detection between 0.625 and 2.5 pg μL for monoamine analytes and their metabolites, including dopamine, 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine, homovanillic acid, norepinephrine, epinephrine, 3-methoxy-4-hydroxyphenylglycol, serotonin and 5-hydroxyindoleacetic acid. Typical concentrations for different monoamines and their metabolization products in these tissues are presented for C57Bl/6 J mice fed a high-fat diet.
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http://dx.doi.org/10.1002/bmc.4151DOI Listing
April 2018

4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate.

J Med Chem 2017 06 25;60(11):4559-4572. Epub 2017 May 25.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00408DOI Listing
June 2017

Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease.

Cell 2016 Oct 6;167(3):843-857.e14. Epub 2016 Oct 6.

Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany.

Glucagon and thyroid hormone (T) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.
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http://dx.doi.org/10.1016/j.cell.2016.09.014DOI Listing
October 2016

Determination of thyroid hormones in mouse tissues by isotope-dilution microflow liquid chromatography-mass spectrometry method.

J Chromatogr B Analyt Technol Biomed Life Sci 2016 Oct 26;1033-1034:413-420. Epub 2016 Aug 26.

Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Molecular EXposomics, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Technische Universität München, Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt, Department für Biowissenschaften, Weihenstephaner Steig 23, 85350 Freising, Germany.

Thyroid hormones (THs) play a critical role in the regulation of many biological processes such as growth, metabolism and development both in humans and wildlife. In general, TH levels are measured by immunoassay (IA) methods but the specificity of the antibodies used in these assays limits selectivity. In the last decade, several analytical methods using liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectrometry (LC-MS/MS) have been developed to measure THs. These new techniques proved to be more accurate than the IA analysis and they were widely used for the determination of TH level in different human and animal tissues. A large part of LC-MS/MS methods described in literature employed between 200 and 500mg of sample, however this quantity can be considered too high especially when preclinical studies are conducted using mice as test subjects. Thus an analytical method that reduces the amount of tissue is essential. In this study, we developed a procedure for the analysis of six THs; L-thyroxine (T4), 3,3',5-triiodo-l-thyronine (T3), 3,3',5'-triiodo-l-thyronine (rT3), 3,5-diiodo-l-thyronine (rT2), 3,3'-diiodo-l-thyronine (T2), 3-iodo-l-thyronine (T1) using isotope ((13)C6-T4, (13)C6-T3, (13)C6-rT3, (13)C6-T2) dilution liquid chromatography-mass spectrometry. The major difference with previously described methods lies in the utilization of a nano-UPLC (Ultra Performance Liquid Chromatography) system in micro configuration. This approach leads to a reduction compared to the published methods, of column internal diameter, flow rate, and injected volume. The result of all these improvements is a decrease in the amount of sample necessary for the analysis. The method was tested on six different mouse tissues: liver, heart, kidney, muscle, lung and brown adipose tissue (BAT). The nano-UPLC system was interfaced with a quadrupole time-of-flight mass spectrometer (Q-TOF2-MS) using the positive ion mode electrospray ionization. In our analytical method the instrumental calibration curves were constructed from 0 to 100pgμL(-1) and all of them showed good linearity (r(2)>0.99). The limit of quantification was from 2.5 to 5pg injected into the column. The method recoveries calculated using spiked mouse liver and spiked mouse muscle were between 83% and 118% (except T1 and rT2 at high concentration) with a coefficient of variation (CV) of <10% for all derivatives. The new methodology allows us to measure T4 and T3 concentrations in a range from 21 to about 100mg and give a more extensive insight on thyroid hormone concentration in different mouse tissue.
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http://dx.doi.org/10.1016/j.jchromb.2016.08.037DOI Listing
October 2016

Identification of (R)-(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor.

J Med Chem 2016 09 8;59(18):8535-48. Epub 2016 Sep 8.

Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.

The synthesis and SAR of a series of 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine P2X7 antagonists are described. Addressing P2X7 affinity and liver microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridines ultimately leading to the identification of 1 (JNJ 54166060). 1 is a potent P2X7 antagonist with an ED50 = 2.3 mg/kg in rats, high oral bioavailability and low-moderate clearance in preclinical species, acceptable safety margins in rats, and a predicted human dose of 120 mg of QD. Additionally, 1 possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00989DOI Listing
September 2016

Preclinical Evaluation of a P2X7 Receptor-Selective Radiotracer: PET Studies in a Rat Model with Local Overexpression of the Human P2X7 Receptor and in Nonhuman Primates.

J Nucl Med 2016 09 19;57(9):1436-41. Epub 2016 May 19.

Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium

Unlabelled: The P2X7 receptor (P2X7R) orchestrates neuroinflammation, and this is the basis for an increased interest in the development of antagonists inhibiting P2X7R function in the brain. This study provides the preclinical evaluation of (11)C-JNJ-54173717, a PET tracer for P2X7R in both rats and nonhuman primates.

Methods: (11)C-JNJ-54173717 is a high-affinity radiotracer for the human P2X7R (hP2X7R). Biodistribution and radiometabolite studies were performed. Viral vectors encoding either enhanced green fluorescent protein-hP2X7R or 3flag-hP2X7R were engineered and validated in cell culture. hP2X7R was regionally overexpressed in the rat striatum after stereotactic injection of viral vectors. Dynamic small-animal PET studies were performed in vector-injected rats and in healthy monkeys using (11)C-JNJ-54173717.

Results: The affinity of JNJ-54173717 was 1.6 ± 0.1 nM in a rat cortex P2X7R membrane binding assay. In a functional assay at the recombinant human and rat P2X7R orthologs, the half maximal inhibitory concentration (IC50) of JNJ-54173717 was 4.2 ± 0.01 nM and 7.6 ± 0.01 nM, respectively. The rat biodistribution study showed that (11)C-JNJ-54173717 crossed the blood-brain barrier and was cleared from plasma mainly via the hepatobiliary pathway. A polar radiometabolite was found in rat plasma. No radiometabolites were detected in rat brain. Dynamic small-animal PET showed binding of (11)C-JNJ-54173717 in the striatum expressing hP2X7R, with rapid washout from the noninjected control striatum and other brain regions. Likewise, (11)C-JNJ-54173717 PET signal was blocked by a chemically distinct P2X7R ligand, indicating specific binding to P2X7R in the monkey brain.

Conclusion: JNJ-54173717 is a high-affinity P2X7R antagonist. An animal rat model stably expressing hP2X7R was developed and validated, identifying favorable characteristics for (11)C-JNJ-54173717 as a PET radioligand for in vivo visualization of hP2X7R. (11)C-JNJ-54173717 selectively visualized P2X7R in the monkey brain, and this radioligand will be further evaluated in a clinical setting to study P2X7R expression levels in neurodegenerative disorders.
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http://dx.doi.org/10.2967/jnumed.115.169995DOI Listing
September 2016

Synthesis, SAR, and Pharmacological Characterization of Brain Penetrant P2X7 Receptor Antagonists.

ACS Med Chem Lett 2015 Jun 24;6(6):671-6. Epub 2015 Apr 24.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

We describe the synthesis and SAR of 1,2,3-triazolopiperidines as a novel series of potent, brain penetrant P2X7 antagonists. Initial efforts yielded a series of potent human P2X7R antagonists with moderate to weak rodent potency, some CYP inhibition, poor metabolic stability, and low solubility. Further work in this series, which focused on the SAR of the N-linked heterocycle, not only increased the potency at the human P2X7R but also provided compounds with good potency at the rat P2X7R. These efforts eventually delivered a potent rat and human P2X7R antagonist with good physicochemical properties, an excellent pharmacokinetic profile, good partitioning into the CNS, and demonstrated in vivo target engagement after oral dosing.
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http://dx.doi.org/10.1021/acsmedchemlett.5b00089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468405PMC
June 2015

Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists.

Bioorg Med Chem Lett 2015 Aug 9;25(16):3157-63. Epub 2015 Jun 9.

Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address:

The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50 = 7.7 nM) and 7u (P2X7 IC50 =7 .7 nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.
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http://dx.doi.org/10.1016/j.bmcl.2015.06.004DOI Listing
August 2015

Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement.

ACS Med Chem Lett 2014 Sep 22;5(9):1049-53. Epub 2014 Jul 22.

Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A. , C/Jarama 75, 45007 Toledo, Spain.

Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 μM. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive impairment and other central nervous system related disorders.
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http://dx.doi.org/10.1021/ml500262uDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160764PMC
September 2014

Synthesis and biological evaluation of carbon-11 and fluorine-18 labeled tracers for in vivo visualization of PDE10A.

Nucl Med Biol 2014 Sep 24;41(8):695-704. Epub 2014 May 24.

Laboratory for Radiopharmacy, KU Leuven, Belgium; MoSAIC, Molecular Small Animal Imaging Centre, KU Leuven, Belgium. Electronic address:

Introduction: In vivo visualization of PDE10A using PET provides a tool to evaluate the role of PDE10A in various neuropsychiatric diseases and can also be useful in the clinical evaluation of PDE10A inhibitor drug candidates. We evaluated several carbon-11 and fluorine-18 labeled PDE10A inhibitors as potential PDE10A PET radioligands.

Materials & Methods: [(11)C]MP10, [(11)C]JNJ42071965 and four other tracers were developed. Their biodistribution was evaluated in rats. Rat plasma and brain radiometabolites were quantified. Baseline microPET imaging was performed in normal rats and PDE10A knockout (KO) and wild-type (WT) mice. Blocking and displacement studies were conducted. The selectivity of the tracer binding was further studied in an ex vivo autoradiography experiment in PDE10A KO and WT mice.

Results: Biodistribution showed brain uptake for all tracers in the striatum and wash-out from the cerebellum. [(11)C]1 ((11)C-MP10) had the highest specific uptake index (striatum (S) vs. cerebellum (C) ratios (S/C)-1) at 60 min (7.4). [(11)C]5 ([(11)C]JNJ42071965) had a high index at the early time points (1.0 and 3.7 at 2 and 30 min p.i., respectively). The affinity of [(11)C]4, [(18)F]3 and [(18)F]6 was too low to visualize PDE10A using microPET. [(11)C] 2 showed a specific binding, while kinetics of [(11)C]1 were too slow. [(11)C]5 reached equilibrium after 10 min (uptake index=1.2). Blocking and displacement experiments in rats and baseline imaging in PDE10A KO mice showed specific and reversible binding of [(11)C]5 to PDE10A.

Conclusions: We successfully radiolabeled and evaluated six radiotracers for their potential to visualize PDE10A in vivo. While [(11)C]1 had the highest striatal specific uptake index, its slow kinetics likely compromise clinical use of this tracer. [(11)C]5 has a relatively high striatum-to-background ratio and fast kinetic profile, which makes it a valuable carbon-11 alternative.
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http://dx.doi.org/10.1016/j.nucmedbio.2014.05.138DOI Listing
September 2014

Discovery of a new series of [1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors.

Bioorg Med Chem Lett 2013 Feb 1;23(3):785-90. Epub 2012 Dec 1.

Janssen Research & Development, Medicinal Chemistry, Janssen-Cilag S.A., C/Jarama 75, 45007 Toledo, Spain.

The synthesis, preliminary evaluation and structure-activity relationship (SAR) of a series of 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors are described. From this investigation compound 31 was identified, showing good combined potency, acceptable brain uptake and high selectivity for both PDE2 and PDE10 enzymes. Compound 31 was subjected to a microdosing experiment in rats, showing preferential distribution in brain areas where both PDE2 and PDE10 are highly expressed. These promising results may drive the further development of highly potent combined PDE2/PDE10 inhibitors, or even of selective inhibitors of PDE2 and/or PDE10.
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http://dx.doi.org/10.1016/j.bmcl.2012.11.077DOI Listing
February 2013

Synthesis, evaluation, and radiolabeling of new potent positive allosteric modulators of the metabotropic glutamate receptor 2 as potential tracers for positron emission tomography imaging.

J Med Chem 2012 Oct 11;55(20):8685-99. Epub 2012 Oct 11.

Medicinal Chemistry, Janssen Research & Development , Janssen-Cilag S.A., C/Jarama 75, 45007 Toledo, Spain.

The synthesis and in vitro and in vivo evaluation of a new series of 7-(phenylpiperidinyl)-1,2,4-triazolo[4,3-a]pyridines, which were conveniently radiolabeled with carbon-11, as potential positron emission tomography (PET) radiotracers for in vivo imaging of the allosteric binding site of the metabotropic glutamate (mGlu) receptor subtype 2 are described. The synthesized compounds proved to be potent and selective positive allosteric modulators (PAMs) of the mGlu receptor 2 (mGluR2) in a [³⁵S]GTPγS binding assay and were able to displace an mGluR2 PAM radioligand, which we had previously developed, with IC₅₀ values in the low nanomolar range. The most promising candidates were radiolabeled and subjected to biodistribution studies and radiometabolite analysis in rats. Preliminary small-animal PET (μPET) studies in rats indicated that [¹¹C]20f binds specifically and reversibly to an mGluR2 allosteric site, strongly suggesting that it is a promising candidate for PET imaging of mGluR2 in the brain.
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http://dx.doi.org/10.1021/jm300912kDOI Listing
October 2012

Recent advances in positron emission tomography (PET) radiotracers for imaging phosphodiesterases.

Curr Top Med Chem 2012 ;12(11):1224-36

Community of Research Excellence & Advanced Technology (CREATe), PET Ligand Discovery, Janssen Research & Development, Janssen-Cilag S.A., C/ Jarama 75, 45007 Toledo, Spain.

Phosphodiesterases (PDEs) are a family of enzymes that metabolically inactivate the second messengers 3',5'- cyclic adenosine monophosphate (cAMP) and/or 3',5'-cyclic guanosine monophosphate (cGMP). These two messengers regulate the extracellular signal from the plasma membrane G protein-coupled receptors (GPCRs) to the intracellular effector proteins, hence modulating a wide variety of biological processes both in the central nervous system (CNS) and peripheral tissues. Although there are many radiotracers available for positron emission tomography (PET) studies of different receptors, there are just a few tracers available for imaging studies of second messenger systems. The first reported PDE PET ligands were the 11C-labeled versions of the PDE4 inhibitors rolipram and Ro 20-1724, and, to date, PET imaging studies in human subjects have only been reported with [11C]rolipram. As a consequence of the growing interest in identifying selective PDE inhibitors as potential new therapeutic agents, new PET radiotracers for imaging specific PDEs have been described in literature as well. This article highlights these efforts on the design and evaluation of novel PET radioligands for in vivo imaging of PDEs.
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http://dx.doi.org/10.2174/156802612800672853DOI Listing
March 2013

Synthesis, in vivo occupancy, and radiolabeling of potent phosphodiesterase subtype-10 inhibitors as candidates for positron emission tomography imaging.

J Med Chem 2011 Aug 2;54(16):5820-35. Epub 2011 Aug 2.

Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag SA, C/Jarama 75, 45007 Toledo, Spain.

We have recently reported the phosphodiesterase 10A (PDE10A) inhibitor 2-[4-[1-(2-[(18)F]fluoroethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenoxymethyl]-quinoline ([(18)F]1a) as a promising candidate for in vivo imaging using positron emission tomography (PET). We now describe the synthesis and biological evaluation of a series of related pyridinyl analogues that exhibit high potency and selectivity as PDE10A inhibitors. The most interesting compounds were injected in rats to measure their levels of PDE10A occupancy through an in vivo occupancy assay. The 3,5-dimethylpyridine derivative 3 and the 5-methoxypyridine derivative 4 showed a comparable level of occupancy to that of 1a. Because these derivatives showed lower in vitro activity and are slightly less lipophilic than 1a, we hypothesized that they could behave as better PET imaging ligands. Compounds [(18)F]3, [(18)F]4, and [(11)C]4 were radiosynthesized and subjected to biodistribution studies in rats for a preliminary evaluation as candidate PET radioligands for in vivo imaging of PDE10A in the brain.
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http://dx.doi.org/10.1021/jm200536dDOI Listing
August 2011

Preclinical evaluation of 18F-JNJ41510417 as a radioligand for PET imaging of phosphodiesterase-10A in the brain.

J Nucl Med 2010 Oct 16;51(10):1584-91. Epub 2010 Sep 16.

Laboratory for Radiopharmacy, Faculty of Pharmaceutical Sciences, K.U. Leuven, Leuven, Belgium.

Unlabelled: Phosphodiesterases are enzymes that inactivate the intracellular second messengers 3',5'-cyclic adenosine-monophosphate and/or cyclic guanosine-monophosphate. Of all 11 known phosphodiesterase families, phosphodiesterase-10A (PDE10A) has the most restricted distribution, with high expression in the striatum. PDE10A inhibitors are pursued as drugs for treatment of neuropsychiatric disorders. We have synthesized and evaluated (18)F-JNJ41510417 as a selective and high-affinity radioligand for in vivo brain imaging of PDE10A using PET.

Methods: The biodistribution of (18)F-JNJ41510417 was evaluated in rats. Rat plasma and perfused brain homogenates were analyzed by high-performance liquid chromatography to quantify radiometabolites. Dynamic small-animal PET was performed in rats and in wild-type and PDE10A knock-out mice and compared with ex vivo autoradiography. Blocking and displacement experiments were performed using the nonradioactive analog and other selective PDE10A inhibitors.

Results: Tissue distribution studies showed predominant hepatobiliary excretion, sufficient brain uptake (0.56 ± 0.00 percentage injected dose at 2 min after tracer injection), and continuous accumulation of the tracer in the striatum over time; rapid washout of nonspecific binding from other brain regions was observed. Polar radiometabolites were detected in plasma and brain tissue. Dynamic small-animal PET showed continuous tracer accumulation in the striatum, with rapid decline in the cortex and cerebellum. Pretreatment and chase experiments with PDE10A inhibitors showed that the tracer binding to PDE10A was specific and reversible. Imaging in PDE10A knock-out and wild-type mice further confirmed that binding in the striatum was specific for PDE10A.

Conclusion: Experiments in rats and PDE10A knock-out mice indicate that (18)F-JNJ41510417 binds specifically and reversibly to PDE10A in the striatum, suggesting that this new fluorinated quinoline derivative is a promising candidate for in vivo imaging of PDE10A using PET.
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http://dx.doi.org/10.2967/jnumed.110.077040DOI Listing
October 2010

Bibenzyl- and stilbene-core compounds with non-polar linker atom substituents as selective ligands for estrogen receptor beta.

Eur J Med Chem 2009 Sep 20;44(9):3412-24. Epub 2009 Feb 20.

Department of Chemistry, University of Illinois, 600 South Matthews Avenue, Urbana, IL 61801, United States.

A series of structurally simple bibenzyl-diol and stilbene-diol core molecules, structural analogs of the well-known hexestrol and diethylstilbestrol non-steroidal estrogens, were prepared and evaluated as estrogen receptor (ER) subtype-selective ligands. Analysis of their ERalpha and ERbeta binding showed that certain substitution patterns engendered binding affinities that were >100-fold selective for ERbeta. When further investigated in cell-based gene transcription assays, some molecules showed similarly high relative transcriptional potency selectivity in favor of ERbeta. Interestingly, the most ERbeta-selective molecules were those bearing non-polar substituents on one of the internal carbon atoms. These compounds should be useful probes for determining the physiological roles of ERbeta, and they might lead to the development of more selective and thus safer pharmaceuticals.
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http://dx.doi.org/10.1016/j.ejmech.2009.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175689PMC
September 2009

Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior.

J Med Chem 2009 Jan;52(1):151-69

European Research Centre for Drug Discovery and Development, University of Siena, Siena, Italy.

Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.
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http://dx.doi.org/10.1021/jm800689gDOI Listing
January 2009