Preclinical studies of potential amyloid binding PET/SPECT ligands in Alzheimer's disease

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Abstract

Visualizing the neuropathological hallmarks amyloid plaques and neurofibrillary tangles of Alzheimer's disease in vivo using positron emission tomography (PET) or single photon emission computed tomography will be of great value in diagnosing the individual patient and will also help in our understanding of the disease. The successful introduction of [11C]PIB as a PET tracer for the amyloid plaques less than 10 years ago started an intensive research, and numerous new compounds for use in molecular imaging of the amyloid plaques have been developed. The candidates are based on dyes like thioflavin T, Congo red and chrysamine G, but also on other types such as benzoxazoles, curcumin and stilbenes. In the present review, we present methods of the radiochemistry and preclinical evaluation as well as the main properties of some of these compounds.

Introduction

Alzheimer's disease (AD) is a common dementing, neurodegenerative disorder which is characterized primarily by deficits in cognition, loss of memory and learning impairment. AD is characterized neuropathologically by the presence of senile amyloid plaques and neurofibrillary tangles, which was demonstrated already by Dr. Alois Alzheimer in 1907 [1]. The plaques are located extracellularly and are mainly composed of β-amyloid (Aβ) peptides in fibrillar form, generated by degradation of the larger amyloid precursor protein (APP) [2], [3]. The intracellularly located tangles mainly consist of filamentous aggregates of polyphosphorylated proteins called tau [4].

The clinical diagnosis of probably AD is normally based on cognitive tests, which limit the diagnosis to a late stage of the disorder. However, amyloid deposits have been demonstrated at an early stage of the disease process, even in the prodromal phase, and they probably occur many years before cognitive symptoms appear [5], [6], [7], [8]. It is therefore of great interest to visualize the development of the amyloid plaques early in the disease process, thereby allowing for the start of treatment as early as possible. During recent years, there has therefore been a rapid development in positron-emitting ligands selectively targeting key histological features in AD to be used in positron emission tomography (PET) in living subjects. One of the first compounds is [11C]PIB, “Pittsburgh compound B” (N-methyl[11C]2-(4′methylaminophenyl)-6-hydroxy-benzothiazole), which was developed from thioflavin T. This early tracer showed significant differences in the level and retention pattern in AD patients compared with controls in areas of the brain known to contain amyloid in AD [9]. [11C]PIB binding was significantly increased in the frontal cortex in patients with AD, and it was also increased in the parietal, temporal and occipital cortices and striatum, while [11C]PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition, such as subcortical white matter, the pons and cerebellum [9], [10].

In the present review, we focus on the development of radiolabeled compounds (“radioligands,” “tracers”) that are used in in vivo molecular imaging studies with PET or single photon emission computed tomography (SPECT). Both techniques are based on introducing short-lived (20 min to a few hours) radionuclides into an amyloid binding molecule. The radionuclides are either emitting positrons (for PET), most often 11C (T1/2: 20 min) or 18F (T1/2: 110 min), or photons (for SPECT), most often 99mTc (T1/2:6.0 h) and 123I (T1/2: 13.2 h). In the evaluation process, long-lived radionuclides, such as tritium (3H, T1/2: 12.3 years) and 125I (T1/2: 59.4 days), may be used in vitro or in in vivo animal studies. PET is today more used than SPECT due to the higher sensitivity and resolution of this technique, and the main proportion of radioligands that are developed for the visualization of amyloid plaques are aimed at PET. This is also evident in the present compilation.

During recent years, the number of compounds targeting the amyloid pathology in AD progression has increased. There are several promising candidates based on highly conjugated dyes such as thioflavin T, Congo red and chrysamine G, but also potential agents of other origin such as benzoxazoles, curcumin and stilbenes. The present literature review has been confined to preclinical studies to clarify the somewhat confusing picture with different chemotypes in the amyloid binding and will only briefly mention the use of the different radioligands in the clinical setting. For studies of the use of the radioligands in the clinic, the reader is referred to one of the several reviews summarizing the clinical use of amyloid binding radioligands from different aspects (see, e.g., Refs. [11], [12], [13]).

Section snippets

Chemical structures

The early attempts to develop Aβ imaging probes were based on the structures of highly conjugated fluorescent staining agents such as Congo red and chrysamine G (Fig. 1), but these probes were not too much successful in vivo due to their low brain penetration ability [14], [15]. During the last several years, a number of other compounds with various chemical structures have been published, including the most successful ([11C]PIB) [16], [17]. The compounds which so far have been explored as

Homogenate binding

Homogenate binding assays may be used for the determination of tracer affinity and selectivity, as well as of amyloid density. Radioligand binding using tissue homogenate cannot be considered a molecular imaging technique, but may certainly be used in the validation of the new imaging tracers. It might be especially useful in connection with synthetic amyloid plaques or Aβ oligomers. However, many of the parameters that can be obtained in homogenate binding studies may be achieved also in in

Thioflavin T

This benzothiazole dye was introduced in the early 1960s and has been used extensively in the diagnosis and presence of amyloid fibrils [66]. The mechanism and specificity however by which thioflavin T binds to amyloid fibrils are somewhat poorly understood. The fact that not all fibrils bind thioflavin T implies a rather complex mechanism. For example, recent models suggest an interaction of the dye with the β-sheet by docking to the surface of cross-stranded ladders formed by certain amino

Conclusions

The diagnosis of AD is dependent mainly upon rating of the cognitive behavior of the patient, and a final diagnosis is obtained only after neuropathological examination. New diagnostic methods using biomarkers are being developed, for example, based on analysis of cerebrospinal fluid (CSF) components [121], [122], [123]. The CSF analyses might indicate the presence of AD, although it has not been clearly stated that the presence of amyloid in the CSF is directly related to the formation of

Acknowledgments

We are grateful for valuable discussions with Prof. Bengt Långström and our other colleagues at Uppsala University and at the Uppsala Applied Science Lab, GE Healthcare. This work was partly performed when two of the authors, O.R. and H.H., were employed at Uppsala Applied Science Lab, GE Healthcare, Uppsala, Sweden. We are grateful to a SAMBIO funding from Vinnova, Sweden.

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