Håkan Hall

In vitro imaging techniques in neurodegenerative diseases

Neurodegeneration induces various changes in the brain, changes that may be investigated using neuroimaging techniques. The in vivo techniques are useful for the visualization of major changes, and the progressing abnormalities may also be followed longitudinally. However, to study and quantify minor abnormalities, neuroimaging of postmortem brain tissue is used. These in vitro methods are complementary to the in vivo techniques and contribute to the knowledge of pathophysiology and etiology of the neurodegenerative diseases. In vitro radioligand autoradiography has given great insight in the involvement of different neuronal receptor systems in these diseases. Data on the dopamine and cholinergic systems in neurodegeneration are discussed in this review. Also, the amyloid plaques are studied using in vitro radioligand autoradiography. Using one of the newer methods, imaging matrix-assisted laser desorption ionization mass spectrometry, the distribution of a large number of peptides and proteins may be detected in vitro on brain cryosections. In this overview, we describe in vitro imaging techniques in the neurodegenerative diseases as a complement to in vivo positron emission tomography and single photon emission computed tomography imaging.

11C and 18FRadiolabeling of Tetra- and Pentathiophenes as PET-ligands for Amyloid Protein Aggregates

Three oligothiophenes were evaluated as PET ligands for the study of local and systemic amyloidosis ex vivo using tissue from patients with amyloid deposits and in vivo using healthy animals and PET-CT. The ex vivo binding studies revealed that all three labeled compounds bound specifically to human amyloid deposits. Specific binding was found in the heart, kidney, liver, and spleen. To verify the specificity of the oligothiophenes toward amyloid deposits, tissue sections with amyloid pathology were stained using the fluorescence exhibited by the compounds and evaluated with multiphoton microscopy. Furthermore, a in vivo monkey PET-CT study showed very low uptake in the brain, pancreas, and heart of the healthy animal indicating low nonspecific binding to healthy tissue. The biological evaluations indicated that this is a promising group of compounds for the visualization of systemic and localized amyloidosis.

Amyloid imaging PET ligands as biomarkers for Alzheimer’s disease : preclinical evaluation

Alzheimer’s disease (AD) is the most common form of dementia in the aging population. It is a complex disease that affects many brain functions and is characterized by a progressive impairment of cognitive abilities, such as memory, learning and social skills. AD was first described over hundred years ago by the German psychiatrist Dr. Alois Alzheimer, reporting of the in due course characteristic pathological changes postmortem discovered in his 56 years old patient Auguste D (Alzheimer, 1907). The disease is obviously devastating for the patients and affects everyday life for both patients and their families, but it also generates economical challenges for the heath-care system and the society as the elderly population is growing (Wimo & Winblad, 2008). Although research regarding AD is intensive worldwide and new results do get a greater understanding of the causes of the disease, the exact mechanisms and underlying cause behind AD are still unsolved. The disease progresses over decades leading to premature death. There are no diseasemodifying therapies for AD available, and the current treatment might provide symptomatic relief and slower disease progression.

Molecular Imaging of Transporters with Positron Emission Tomography

Positron emission tomography (PET) visualization of brain components in vivo is a rapidlygrowing field. Molecular imaging with PET is also increasingly used in drug development, especiallyfor the determination of drug receptor interaction for CNS-active drugs. This gives the opportunityto relate clinical efficacy to per cent receptor occupancy of a drug on a certain targetedreceptor and to relate drug pharmacokinetics in plasma to interaction with target protein. In thepresent review we will focus on the study of transporters, such as the monoamine transporters, theP-glycoprotein (Pgp) transporter, the vesicular monoamine transporter type 2, and the glucosetransporter using PET radioligands. Neurotransmitter transporters are presynaptically located andin vivo imaging using PET can therefore be used for the determination of the density of afferent neurons.Several promising PET ligands for the noradrenaline transporter (NET) have been labeled and evaluatedin vivo including in man, but a really useful PET ligand for NET still remains to be identified.The most promising tracer to date is (S,S)-[18F]FMeNER-D2.The in vivo visualization of the dopamine transporter (DAT) may give clues in the evaluation of conditionsrelated to dopamine, such as Parkinsons disease and drug abuse. The first PET radioligands basedon cocaine were not selective, but more recently several selective tracers such as [11C]PE2Ihave been characterized and shown to be suitable as PET radioligands. Although there are a largenumber of serotonin transporter inhibitors used today as SSRIs, it was not until very recently, when[11C]McN5652 was synthesized, that this transporter was studied using PET.New candidates as PET radioligands for the SERT have subsequently been developed and [11C]DASBand [11C]MADAM and their analogues are today the most promising ligands.The existing radioligands for Pgp transporters seem to be suitable tools for the study of both peripheraland central drug–Pgp interactions, although [11C]verapamil and [18F]fluoropaclitaxelare probably restricted to use in studies of the blood–brain barrier. The vesicular monoaminetransporter 2 (VMAT2) is another interesting target for diagnostic imaging and [11C]DTBZis a promising tracer. The noninvasive imaging of transporter density as a function ofdisease progression or availability following interaction with blocking drugs is highlighted, includingthe impact on both development of new therapies and the process of developing new drugs. AlthoughCNS-related work focusing on psychiatric disorders is the main focus of this review, other applicationsof PET ligands, such as diagnosis of cancer, diabetes research, and drug interactions with effluxsystems, are also discussed. The use of PET especially in terms of tracer development is brieflydescribed. Finally, it can be concluded that there is an urgent need for new, selective radioligandsfor the study of the transporter systems in the human brain using PET.