Decreased defluorination using the novel beta-cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET

The aim of the thesis was twofold. The first aim was to radiolabel small molecules by using carbon-11 and fluorine-18 for visualising beta cell mass (BCM) in the pancreas by PET. Diabetes Mellitus (DM) is a chronic metabolic disorder that results from an absolute or relative lack of BCM of endocrine pancreas. The lack of an adequate non-invasive imaging PET probe prevents detailed examination of beta cell loss during onset and progression of DM as well as development of novel treatments and islets transplantation progress. The second aim of the thesis was to radiolabel peptide molecules with fluorine-18 to visualise beta amyloid in Alzheimer’s disease (AD) brain. AD is a chronic, progressive neurodegenerative disorder. Brain penetration study of a labelled peptide, specific for beta amyloid that can cross blood-brain-barrier (BBB), is important to gain knowledge about the fate of the molecule as a diagnostic probe. A series of three novel radioligands for BCM imaging has been developed in this thesis. In paper I, a vesicular monoamine transporter type 2 (VMAT2) specific radioligand [18F]FE-DTBZ-d4 was synthesised in two steps. First step is the nucleophilic [18F]fluorination to produce deuterated-[18F]fluoroethylbromide followed by the O- alkylation of desmethyl-DTBZ precursor to produce [18F]FE-DTBZ-d4. The in vivo pharmacokinetics (PK) studies in pigs by PET/CT demonstrated reduced in vivo defluorination; therefore, it may be an improved potential candidate for imaging VMAT2 dense tissue i.e. islets transplantation in proximity to cortical bone structure. In Paper II, a glucokinase (GK) specific radioligand, [11C]AZ12504948, was synthesised in one step via alkylation of O-desmethyl precursor using [11C]methyl iodide. Both in vitro and in vivo (pig and monkey) studies with [11C]AZ12504948 for imaging GK in the pancreas and liver indicated low specificity. Increased target specificity is required for further progress in GK imaging using PET radioligands. In Paper III, a radioligand for G-protein coupled receptor 44 (GPR44), [11C/3H]AZ Compound X, was synthesised via S-methylation of sodium sulfinate salt in one step using [11C/3H]methyl iodide. In vitro binding of the radioligand, evaluated by autoradiography (ARG) on human and rat pancreatic tissues, confirmed higher specific binding in islets of human pancreatic tissue and no measurable binding in rat pancreas, which is devoid of GPR44. These studies indicate that the radioligand has suitable properties for beta cell imaging with high potential for further preclinical and clinical evaluation. Three novel D-peptides were radiolabelled with fluorine-18 ([18F]ACI-87, [18F]ACI- 88, [18F]ACI-89) by using prosthetic group N-succinimidyl-4-[18F]fluorobenzoate, [18F]SFB, with epsilon (ε)-amino groups of lysine residues of peptide precursors in two steps. First step is the synthesis of [18F]SFB followed by the addition of [18F]SFB via acylation to the peptide molecule. Trimethylammonium salt [N(CH3)3+] precursor for synthesising [18F]SFB as well as the reference standard SFB were synthesised with good yields. Three 19F-peptide reference standards were also synthesised by using SFB. Preliminary ARG measurements were performed in AD and control human brains. ARG demonstrated higher radioligand uptake in the AD brain compared to age-matched control brain, which makes them potential for further use in in vivo testing by PET. However, preliminary PET (in vivo) studies in cynomolgus monkey brain, using these 18F-D-peptides, confirmed too low BBB penetration, making them unsuitable for further use as in vivo PET probes

Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects

Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation. This study investigated if the pharmacokinetic differences translate into different time curves for central D2 dopamine receptor occupancy. Eleven control subjects were examined with positron emission tomography (PET) and the radioligand [11C]raclopride. Eight subjects underwent all of the scheduled PET measurements. After baseline examination, quetiapine XR was administered once-daily for 8 d titrated to 300 mg/d on days 5–8, followed by 300 mg/d quetiapine IR on days 9–12. PET measurements were repeated after the last doses of quetiapine XR and IR at predicted times of peak and trough plasma concentrations. Striatal D2 receptor occupancy was calculated using the simplified reference tissue model. Peak D2 receptor occupancy was significantly higher with quetiapine IR than XR in all subjects (50±4% and 32±11%, respectively), consistent with lower peak plasma concentrations for the XR formulation. Trough D2 receptor occupancy was similarly low for both formulations (IR 7±7%, XR 8±6%). The lower peak receptor occupancy associated with quetiapine XR may explain observed pharmacodynamic differences between the formulations. Assuming that our findings in control subjects are valid for patients with schizophrenia, the study supports the view that quetiapine, like the prototype atypical antipsychotic clozapine, may show antipsychotic effect at lower D2 receptor occupancy than typical antipsychotics

The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer’s disease: a post-mortem autoradiographic study.

Earlier post-mortem histological and autoradiographic studies have indicated a reduction of cell numbers in the locus coeruleus (LC) and a corresponding decrease in norepinephrine transporter (NET) in brains obtained from Alzheimer's disease (AD) patients as compared to age-matched healthy controls. In order to test the hypothesis that the regional decrease of NET is a disease specific biomarker in AD and as such, it can be used in PET imaging studies for diagnostic considerations, regional differences in the density of NET in various anatomical structures were measured in whole hemisphere human brain slices obtained from AD patients and age-matched control subjects in a series of autoradiographic experiments using the novel selective PET radioligand for NET (S,S)-[F-18]FMeNER-D-2. (S,S)-[F-18]FMeNER-D-2 appears to be a useful imaging biomarker for quantifying the density of NET in various brain structures, including the LC and the thalamus wherein the highest densities are found in physiological conditions. In AD significant decreases of NET densities can be demonstrated with the radioligand in both structures as compared to age-matched controls. The decreases in AD correlate with the progress of the disease as indicated by Braak grades. As the size of the LC is below the spatial resolution of the PET scanners, but the size of the thalamus can be detected with appropriate spatial accuracy in advanced scanners, the present findings confirm our earlier observations with PET that the in vivo imaging of NET with (S,S)-[F-18]FMeNER-D-2 in the thalamus is viable. Nevertheless, further studies are warranted to assess the usefulness of such an imaging approach for the early detection of changes in thalamic NET densities as a disease-specific biomarker and the possible use of (S,S)-[F-18]FMeNER-D-2 as a molecular imaging biomarker in AD. (c) 2010 Elsevier Ltd. All rights reserved

Scale setting for Nf=3+1N_f=3+1 QCD

We present the scale setting for a new set of gauge configurations generated with $N_f=3+1$ Wilson quarks with a non-perturbatively determined clover coefficient in a massive O($a$) improvement scheme. The three light quarks are degenerate, with the sum of their masses being equal to its value in nature and the charm quark has its physical mass. We use open boundary conditions in time direction to avoid the problem of topological freezing at small lattice spacings and twisted-mass reweighting for improved stability of the simulations. The decoupling of charm at low energy allows us to set the scale by measuring the value of the low-energy quantity $t_0^\star/a^2$, which is the flow scale $t_0$ at our mass point, and comparing it to an $N_f=2+1$ result in physical units. We present the details of the algorithmic setup and tuning procedure and give the bare parameters of ensembles with two lattice spacings a=0.054 fm and a=0.043 fm. We discuss finite volume effects and lattice artifacts and present physical results for the charmonium spectrum. In particular the hyperfine splitting between the $\eta_c$ and $J/\psi$ mesons agrees very well with its physical value.Comment: 25 pages, 9 figures. Version accepted for publication in the European Physical Journal

Associations between cognition and serotonin receptor 1B binding in patients with major depressive disorder : a pilot study

The neurotransmitter serotonin has been widely implicated in the pathophysiology of major depressive disorder (MDD). In animal studies and human neuroimaging studies, involvement of the serotonin receptor 1B (5-HT1BR) in MDD and memory performance has been reported. However, the role of the 5-HT1BR in cognitive functions affected in MDD remains to be clarified. Ten patients with MDD diagnosis were examined with positron emission tomography (PET) and a battery of cognitive tests before and after Internet-based Cognitive Behavioral Therapy (ICBT). The results were compared to ten matched control subjects in order to investigate putative changes in 5-HT1BR availability and cognitive performance. Patients treated with ICBT showed statistically significant improvement relative to baseline in Verbal fluency, both letter and category production. Significant correlations were found between improvement in letter production and changes in 5-HT1BR availability in ventral striatum, between category production and amygdala, as well as between the improvement in Trailmaking test B and change in 5-HT1BR binding in dorsal brainstem, in amygdala and in hippocampus. The results suggest an association between 5-HT1BR binding and improvement in cognitive functioning. Replications in larger-scale studies are required to confirm these findings.Swedish Research Council (523-2013-2982)Birgitta and Sten WesterbergSwedish Society of MedicineStiftelsen Söderström-Königska sjukhemmetStockholm County CouncilThe Stockholm Centre for Psychiatric ResearchKarolinska InstitutetAccepte

ABC transporter-dependent brain uptake of the 5-HT1B receptor radioligand [C-11]AZ10419369:a comparative PET study in mouse, rat, and guinea pig

BACKGROUND: We have explored the possibility that the serotonin 1B receptor radioligand [(11)C]AZ10419369 is a substrate for adenosine triphosphate (ATP)-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), Mrp4, and Bcrp, in rodents and whether there is a species difference regarding its blood-brain barrier (BBB) penetration. METHODS: In a series of preclinical positron emission tomography measurements, we have administered [(11)C]AZ10419369 to mice, rats, and guinea pigs under baseline conditions and, on separate experimental days, after administration of the ABC transporter inhibitor, cyclosporin A (CsA). RESULTS: During baseline conditions, the brain uptake was low in mice and rats, but not in guinea pigs. After CsA pretreatment, the peak whole brain uptake values of [(11)C]AZ10419369 increased by 207% in mice, 94% in rats, and 157% in guinea pigs. Binding potentials (BP(ND)) could not be estimated during baseline conditions in mice and rats. After CsA pretreatment, the highest BP(ND) values were obtained in the striatum and thalamus (BP(ND) ≈ 0.4) in mice, while in rats, the highest binding areas were the striatum, thalamus, hypothalamus, and periaqueductal gray (BP(ND) ≈ 0.5). In guinea pigs, we did not find any significant changes in BP(ND) between baseline and CsA pretreatment, except in the striatum. CONCLUSIONS: The results indicate that BBB penetration of [(11)C]AZ10419369 was hindered by ABC transporter activity in mouse, rat, and guinea pig. This study highlights the importance of ABC transporters in the design of preclinical positron emission tomography (PET) studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13550-014-0064-0) contains supplementary material, which is available to authorized users

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28.

Abstract Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia