Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand 11C-PIB

Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand ¹¹C-PIB Accumulation of beta amyloid (Abeta) in the brain is characteristic for Alzheimer’s disease (AD). Carbon-11 labeled 2-(4’-methylaminophenyl)-6-hydroxybenzothiazole (¹¹C-PIB) is a novel positron emission tomography (PET) amyloid imaging agent that appears to be applicable for in vivo Abeta plaque detection and quantitation. The biodistribution and radiation dosimetry of ¹¹C-PIB were investigated in 16 healthy subjects. The reproducibility of a simplified ¹¹C-PIB quantitation method was evaluated with a test-retest study on 6 AD patients and 4 healthy control subjects. Brain ¹¹C-PIB uptake and its possible association with brain atrophy rates were studied over a two-year follow-up in 14 AD patients and 13 healthy controls. Nine monozygotic and 8 dizygotic twin pairs discordant for cognitive impairment and 9 unrelated controls were examined to determine whether brain Abeta accumulation could be detected with ¹¹C-PIB PET in cognitively intact persons who are at increased genetic risk for AD. The highest absorbed radiation dose was received by the gallbladder wall (41.5 mjuGy/MBq). About 20 % of the injected radioactivity was excreted into urine, and the effective whole-body radiation dose was 4.7 mjuSv/MBq. Such a dose allows repeated scans of individual subjects. The reproducibility of the simplified ¹¹C-PIB quantitation was good or excellent both at the regional level (VAR 0.9-5.5 %) and at the voxel level (VAR 4.2-6.4 %). ¹¹C-PIB uptake did not increase during 24 months’ follow-up of subjects with mild or moderate AD, even though brain atrophy and cognitive decline progressed. Baseline neocortical ¹¹C-PIB uptake predicted subsequent volumetric brain changes in healthy control subjects (r = 0.725, p = 0.005). Cognitively intact monozygotic co-twins – but not dizygotic co-twins – of memory-impaired subjects exhibited increased ¹¹C-PIB uptake (117-121 % of control mean) in their temporal and parietal cortices and the posterior cingulate (p<0.05), when compared with unrelated controls. This increased uptake may be representative of an early AD process, and genetic factors seem to play an important role in the development of AD-like Abeta plaque pathology. ¹¹C-PIB PET may be a useful method for patient selection and follow-up for early-phase intervention trials of novel therapeutic agents. AD might be detectable in high-risk individuals in its presymptomatic stage with ¹¹C-PIB PET, which would have important consequences both for future diagnostics and for research on disease-modifying treatments.

Kehittyneiden ydinpolttoainekiertojen ympäristövaikutusten ja taloudellisuuden arviointia

Kaikkein yleisin käytössä oleva ydinpolttoainekierto on nykyisin avoin, jossa käytetty ydinpolttoaine loppusijoitetaan suoraan ilman jälleenkäsittelyä. Nykyisin kehitteillä olevat uuden sukupolven ydinreaktorit ovat kuitenkin pääosin suunniteltu osittain tai kokonaan suljetuille ydinpolttoainekierroille, jossa käytetty polttoaine jälleenkäsitellään ja osa materiaaleista kierrätetään. Tämän työn tavoitteena oli arvioida näitä kehittyneitä ydinpolttoainekiertoja ympäristövaikutusten ja taloudellisuuden suhteen. Työn yleisluonteista vertailua varten valittiin neljä erilaista kehittynyttä polttoainekiertoskenaariota, joita verrattiin avoimeen polttoainekiertoon erilaisten parametrien avulla. Parametreinä käytettiin muun muassa uraanin kulutusta, loppusijoitettavan jätteen määrää, aktiivisuutta ja lämmöntuottoa sekä käytönaikaisten radioaktiivisten päästöjen määrää. Yleislounteisen arvioinnin lisäksi työssä tarkasteltiin polttoainekiertoa myös Suomen näkökulmasta. Nykyistä polttoainekiertoa verrattiin kahteen erilaiseen tulevaisuuden versioon. Kestävän kehityksen osalta kehittyneet polttoainekierrot vähensivät ympäristövaikutusten määrää avoimeen polttoainekiertoon verrattuna. Kehittyneiden polttoainekiertojen kustannukset olivat avoimen polttoainekierron kustannuksia suuremmat. Kokonaiskustannuksissa ero oli kaikilla vertailuskenaarioilla alle 20 %, mutta polttoainekiertokustannuksissa kustannusten kasvu oli välillä 27-45 % riippuen skenaariosta. Suomen tapauksessa tulokset olivat hyvin samankaltaisia. Uraanin kulutus ja loppusijoitettavan jätteen määrä väheni kehittyneempien polttoainekiertojen johdosta. Polttoainekiertokustannukset nousivat noin puolitoistakertaisiksi, mutta vaikutus kokonaiskustannuksiin oli vain noin 10 %. Johtopäätöksenä voidaan todeta, ettäydinpolttoainekierron ympäristövaikutuksia on mahdollista vähentää osittain tai kokonaan suljettujen polttoainekiertojen avulla. Vaikka polttoainekierron kustannukset kasvavat, niiden vaikutus ydinsähkön kokonaiskustannuksiin ei ole niin merkittävä.

18F-Labeled Presynaptic Dopaminergic Tracers. Synthesis, Radiochemical Analyses, and Preclinical Evaluation of [18F]FDOPA and [18F]CFT

Dysfunction of the dopaminergic system in brain is involved in several pathological conditions such as Parkinson’s disease and depression. 2β-Carbomethoxy-3β-(4-[18F] fluorophenyl)tropane ([18F]CFT) and 6-[18F]fluoro-L-dopa ([18F]FDOPA) are tracers for imaging the dopaminergic function with positron emission tomography (PET). Peripheral uptake of [18F]FDOPA is also used in the localization and diagnosis of neuroendocrine tumors. [18F]FDOPA and [18F]CFT can be synthesized by electrophilic fluorodestannylation. However, the specific radioactivity (SA) in the electrophilic fluorination is low with traditional synthetic methods. In this study, [18F]FDOPA and [18F]CFT were synthesized using post-target-produced [18F]F2 as an electrophilic fluorination agent. With this method, tracers are produced with sufficient SA for neuroreceptor studies. Specific aims in this study were to replace Freon-11 in the production of [18F]FDOPA due to the ozone depleting properties of this solvent, to determine pharmacological specificity and selectivity of [18F]CFT with respect to monoamine transporters, and to compare the ability of these tracers to reflect the degree of nigral neuronal loss in rats in which the dopaminergic system in the brain had been unilaterally destroyed by 6- OHDA. Post-target-produced [18F]F2 was successfully used in the production of [18F]FDOPA and [18F]CFT. The SA achieved was substantially higher than in previous synthetic methods. Deuterated compounds, CD2Cl2, CDCl3 and C3D6O, were found to be suitable solvents for replacing Freon-11. Both [18F]FDOPA and [18F]CFT demonstrated nigrostriatal dopaminergic hypofunction and correlated with the number of nigral dopaminergic neurons in the 6-OHDA lesioned rat. However, the dopamine transporter (DAT) tracer [18F]CFT was more sensitive than the dopamine synthesis tracer [18F]FDOPA in detecting these defects because of the higher non-specific uptake of [18F]FDOPA. [18F]CFT can also be used for imaging the norepinephrine transporter (NET) because of the specific uptake into the locus coeruleus. The observation that [18F]CFT exhibits specific uptake in the pancreas warrants further studies in humans with respect to potential utility in pancreatic imaging

Homogeneous assay technologies in drug screening: Quenching Resonance Energy Transfer (QRET) technique

Information gained from the human genome project and improvements in compound synthesizing have increased the number of both therapeutic targets and potential lead compounds. This has evolved a need for better screening techniques to have a capacity to screen number of compound libraries against increasing amount of targets. Radioactivity based assays have been traditionally used in drug screening but the fluorescence based assays have become more popular in high throughput screening (HTS) as they avoid safety and waste problems confronted with radioactivity. In comparison to conventional fluorescence more sensitive detection is obtained with time-resolved luminescence which has increased the popularity of time-resolved fluorescence resonance energy transfer (TR-FRET) based assays. To simplify the current TR-FRET based assay concept the luminometric homogeneous single-label utilizing assay technique, Quenching Resonance Energy Transfer (QRET), was developed. The technique utilizes soluble quencher to quench non-specifically the signal of unbound fraction of lanthanide labeled ligand. One labeling procedure and fewer manipulation steps in the assay concept are saving resources. The QRET technique is suitable for both biochemical and cell-based assays as indicated in four studies:1) ligand screening study of β2 -adrenergic receptor (cell-based), 2) activation study of Gs-/Gi-protein coupled receptors by measuring intracellular concentration of cyclic adenosine monophosphate (cell-based), 3) activation study of G-protein coupled receptors by observing the binding of guanosine-5’-triphosphate (cell membranes), and 4) activation study of small GTP binding protein Ras (biochemical). Signal-to-background ratios were between 2.4 to 10 and coefficient of variation varied from 0.5 to 17% indicating their suitability to HTS use.