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

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.publisher: Elsevier articletitle: Synthesis and biological evaluation of carbon-11 and fluorine-18 labeled tracers for in vivo visualization of PDE10A journaltitle: Nuclear Medicine and Biology articlelink: http://dx.doi.org/10.1016/j.nucmedbio.2014.05.138 content_type: article copyright: Copyright © 2014 Elsevier Inc. All rights reserved.status: publishe

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

Aims/hypothesis Treatment with the alpha 3 beta 4 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 beta 4-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

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

ims/hypothesisTreatment with theα3β4 nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), improves glucose tolerance in diet-induced obese (DIO) mice, but the physiological andmolecular mechanisms are unknown.MethodsDMPP (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) andChrnb4knockout (KO) mice and glucose tolerance, tissue-specific tracer-based glucosemetabolism, and insulin signalling were assessed.ResultsIn WT mice, but not inChrnb4KO mice, single acute treatment with DMPP induced transient hyperglycaemia,which was accompanied by high plasma adrenaline (epinephrine) levels, upregulated hepatic gluconeogenic genes, anddecreased hepatic glycogen content. In contrast to theseacute effects, chronic DMPP treatment in WT mice elicitedimprovements in glucose tolerance already evident after three consecutive days of DMPP treatment. After seven days ofDMPP treatment, glucose tolerance was markedly improved,alsoincomparisonwithmicethatwerepair-fedtoDMPP-treated mice. The glycaemic benefit of chronic DMPP was absent inChrnb4KO mice. Chronic DMPP increased insulin-stimulated glucose clearance into brown adipose tissue(+69%), heart (+93%), gastrocnemius muscle (+74%) andquadriceps muscle (+59%), with no effect in white adipose tissues. After chronic DMPP treatment, plasma adrenalinelevels did not increase following an injection with DMPP. In glucose-stimulated skeletal muscle, we detected a decreasedphosphorylation of the inhibitory Ser640 phosphorylation site on glycogen synthase and a congruent increase in glyco-gen accumulation following chronic DMPP treatment.Conclusions/interpretationOur data suggest that DMPP acutely induces adrenaline release and hepatic glycogenolysis,while chronic DMPP-mediated activation ofβ4-containing nAChRs improves peripheral insulin sensitivity independent-ly of changes in body weight via mechanisms that could involve increased non-oxidative glucose disposal into skeletalmuscle.publishe

Supplemental Data_2018_06_04

The supplemental material of manuscript "Association of In Utero Persistent Organic Pollutant Exposure with Placental Thyroid Hormones". Supplemental method, Supplemental Table 1, Supplemental Table 2, Supplemental Table

Association of in Utero Persistent Organic Pollutant Exposure with Placental Thyroid Hormones

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), T 4, T 3, and rT 3 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, T 4, T 3, and rT 3 were measured. No correlation between THs and the odds of cryptorchidism was found. Several POPs were significantly associated with THs: (1) T 4 was inversely associated with BDEs 99, 100, Σ PBDE, and 2378-TeCDD, and positively associated with 1234678-HpCDF; (2) T 3 was positively associated with 2378-TeCDF and 12378-PeCDF; and (3) rT 3 was positively associated with PCB 81, 12378-PeCDF, and 234678-HxCDF, and inversely associated with tributyltin, Σ OTC, 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

Data from: Association of in utero persistent organic pollutant exposure with placental thyroid hormones

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 present study was performed to investigate the associations between placental levels of various POPs and thyroid hormones (THs). In a prospective Danish study initially established for assessing congenital cryptorchidism, 58 placenta samples were collected from mothers of boys born with (28) and without (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), thyroxine (T4), 3,3’,5-triiodothyronine (T3), and 3,3’,5’-triiodothyronine (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: a) T4 was inversely associated with BDEs 99, 100, ΣPBDE, and 2378-TeCDD, and positively associated with 1234678-HpCDF; b) T3 was positively associated with 2378-TeCDF and 12378-PeCDF; c) rT3 was positively associated with PCB 81, 12378-PeCDF and 234678-HxCDF, and inversely associated with tributyltin (TBT), ΣOTC, and methoxychlor (MOC). These results revealed that POP exposures were associated with TH levels in placenta, 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

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

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 (T4), 3,3',5-triiodo-l-thyronine (T3), 3,3',5'-triiodo-l-thyronine (rT3), 3,3'-diiodo-l-thyronine (T2), 3,5-diiodo-l-thyronine (rT2), 3-iodo-l-thyronine (T1) and 3-iodothyronamine (T1AM), in placenta using isotope dilution liquid chromatography quadrupole time-of-flight mass spectrometry. We optimized the method using isotopically labeled quantification standards (13C6-T4, 13C6-T3, 13C6-rT3 and 13C6-T2) and recovery standard (13C12-T4) 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-1 with R2 values >0.99. The method detection limits (MDLs) ranged from 0.01 ng g-1 to 0.2 ng g-1, while the method quantification limits (MQLs) were between 0.04 ng g-1 and 0.7 ng g-1. The spike-recoveries for THs (except for T1 and T1AM) 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-1 T4, 0.32-0.46 ng g-1 T3, 2.86-3.69 ng g-1 rT3, 0.16-0.26 ng g-1 T2, and < MDL for other THs in five human placentas, and 2.05-3.51 ng g-1 T4, 0.37-0.62 ng g-1 T3, 0.96-1.3 ng g-1 rT3, 0.07-0.13 ng g-1 T2 and < MDL for other THs in five mouse placentas. The presence of T2 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