What is an exhibition? Dealing with how people experience art, artistic works, making art and the appreciation of things, via a contextualisation of Allen Carlson and Emmanuel Kant aesthetic ideas and 21st century art theory.

This written thesis is an observation on Allen Carlson, and Emmanuelle Kant’s aesthetic theories alongside and observation of art and the everyday. The main focus of the research is to gain a better understanding surrounding these topic matters, concerning our experience of art in relation to the experience of our surrounding. As such does our experience become affected when participating in specific activates

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

Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [C-11]PBR28 and Machine Learning Analysis

Background The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. Objective In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA.Methods We analyzed [C-11]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. Results We observed a conspicuous pattern of elevated regional [C-11]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. Conclusions We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an alpha-synucleinopathy that remains strikingly incurable. </p

EDITORIAL

This themed section on Imaging in Pharmacology comprising reviews and original articles arose from two symposia held at the Summer Meeting of the British Pharmacological Society in Edinburgh 8–10 July 2009 on Developments in Receptor Imaging and Imaging and Targeting Inflammation in Stroke and Atherosclerosis. The reports cover a broad spectrum of pharmacological studies, from whole animal imaging to gene expression and emphasize the importance of imaging techniques in pharmacology. The development of each new imaging methodology brings pharmacology closer to the ambitious goal of being able to image (simultaneously) each component part of the G-protein-coupled receptor signalling process

Toward molecular imaging of the free fatty acid receptor 1

Molecular imaging of the free fatty acid receptor 1 (FFAR1) would be a valuable tool for drug development by enabling in vivo target engagement studies in human. It has also been suggested as a putative target for beta cell imaging, but the inherent lipophilicity of most FFAR1 binders produces high off-target binding, which has hampered progress in this area. The aim of this study was to generate a suitable lead compound for further PET labeling. In order to identify a lead compound for future PET labeling for quantitative imaging of FFAR1 in human, we evaluated tritiated small molecule FFAR1 binding probes ([H-3]AZ1, [H-3]AZ2 and [H-3]TAK-875) for their off-target binding, receptor density and affinity in human pancreatic tissue (islets and exocrine) and rodent insulinoma. [H-3]AZ1 showed improved specificity to FFAR1, with decreased off-target binding compared to [H-3]AZ2 and [H-3]TAK-875, while retaining high affinity in the nanomolar range. FFAR1 density in human islets was approximately 50% higher than in exocrine tissue. AZ1 is a suitable lead compound for PET labeling for molecular imaging of FFAR1 in humans, due to high affinity and reduced off-target binding

Positron emission tomography using (18)F-labelled endothelin-1 reveals prevention of binding to cardiac receptors owing to tissue-specific clearance by ET(B) receptors in vivo

1. Our aim was to synthesise an (18)F analogue of endothelin-1 (ET-1), to dynamically image ET receptors in vivo by positron emission tomography (PET) and to elucidate the function of the ET(B) subtype as a clearing receptor in organs expressing high densities including kidney and lung. 2. [(18)F]-ET-1 was characterised in vitro and bound with a single subnanomolar affinity (K(D)=0.43±0.05 nM, B(max)=27.8±2.1 fmol mg(−1) protein) to human left ventricle (n=4). 3. The in vivo distribution of [(18)F]-ET-1 in anaesthetised rats was measured using a dedicated small animal PET scanner (microPET) and ex vivo analysis. 4. Dynamic PET data demonstrated that high levels of radioligand accumulated rapidly in the lung, kidney and liver, consistent with receptor binding. The in vivo distribution correlated with the anatomical localisation of receptors detected in vitro using [(125)I]-ET-1. However, the receptor density visualised in the heart was unexpectedly low compared with that predicted from the in vitro measurements. 5. [(18)F]-ET-1 binding in lungs could not be displaced by the ET(B) selective antagonist BQ788, in agreement with the proposed internalisation of ET-1 by ET(B) receptors. In contrast, infusion of BQ788 prior to injecting [(18)F]-ET-1 significantly reduce the amount of radioligand visualised in the ET(B) rich lung and kidney by 85% (P<0.05, n=3) and 55% (P<0.05, n=3), respectively. 6. Under conditions of ET(B) receptor blockade, the heart could be visualised by microPET imaging. 7. These results suggest that clearance by ET(B) receptors in the lung and kidney prevents binding of ET-1 to receptors in the heart