Impact of amyloid imaging on drug development in Alzheimer's disease☆

https://doi.org/10.1016/j.nucmedbio.2007.06.015Get rights and content

Abstract

Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Aβ plaques in the brain as well as to help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Aβ imaging agents are currently underway. We reported the first PET studies of the carbon 11-labeled thioflavin-T derivative Pittsburgh Compound B in 2004, and this work has subsequently been extended to include a variety of subject groups, including AD patients, mild cognitive impairment patients and healthy controls. The ability to quantify regional Aβ plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.

Introduction

Alzheimer's disease (AD) is the most prevalent cause of dementia, accounting for 60–70% of all dementia cases, and there were about 4.5 million people afflicted with AD in the United States in 2000 [1]. The most significant risk factor for developing AD is age, with a prevalence rate of about 30% by 85 years [2], and increased longevity is expected to raise the number of cases in the United States to more than 13 million by 2050 [1]. These numbers highlight the need for more effective therapeutic interventions for AD beyond presently used drugs. Currently used drugs, such as cholinesterase inhibitors and NMDA (N-methyl-d-aspartate) receptor antagonists, treat the symptoms of AD but do not halt or reverse the pathophysiological causes of AD. An imaging agent that could provide direct evidence of the delay or reversal of the root cause(s) of AD could hasten drug development and intervention efforts and assist in delivering therapies that are truly effective in delaying the onset or modifying the progression of AD.

AD is characterized histopathologically by the presence and abundance of two abnormal aggregated proteins in brain tissue: amyloid plaques and neurofibrillary tangles (NFTs) (Fig. 1) [3]. Amyloid plaques are predominantly composed of insoluble amyloid-beta (Aβ) peptides, mostly 40 or 42 amino acids in length, with Aβ42 being the most prevalent component [4]. NFTs are composed mainly of hyperphosphorylated forms of the microtubule-associated protein tau [5]. Most investigators referring to “amyloid” in AD equate the term to Aβ, but “amyloid” is a more general term and refers to many types of β-pleated sheet conformation proteins found both systemically and in the central nervous system [6], [7]. A recent report by the International Society of Amyloidosis Nomenclature Committee defined amyloids as “extracellular depositions of protein fibrils with characteristic appearance in electron microscope, typical X-ray diffraction pattern, and affinity for Congo red with concomitant green birefringence” [8]. By this definition, Aβ plaques, as well as prion proteins associated with spongiform encephalopathies (e.g., mad cow disease and scrapie), are amyloid proteins. However, NFTs and Lewy bodies (composed mainly of α-synuclein protein) are not amyloids; instead, they are defined as “close relatives” of amyloids because of their predominantly intracellular or intraneuronal locations. In AD, the Aβ component far outweighs the other amyloid-related protein components, such as NFTs, on a total mass basis in most brain regions [9]. This presents more binding sites (higher Bmax) for aggregated Aβ binding relative to NFT binding sites for ligands with high binding affinities for these protein deposits. It is interesting and important that some thioflavin-T derivatives, such as Pittsburgh Compound B (PiB) [2-(4′-methylaminophenyl)-6-hydroxybenzothiazole] (Fig. 2), bind fibrillar Aβ deposits with no detectable binding to soluble Aβ forms and to NFTs or Lewy bodies [10] under conditions relevant to positron emission tomography (PET) studies (at ligand concentrations ∼1 nM).

Section snippets

Potential uses of an Aβ imaging agent

Several potential uses of Aβ radioligands labeled with positron-emitting or single photon-emitting radionuclides are evident: the first is their use as imaging agents to diagnose AD. While Aβ plaques are one of the characteristic features of AD confirmed by postmortem evaluation (Fig. 1), Aβ deposition in the brain is not unique to clinically apparent AD and has been found in normal aging, prompting the suggestion that there is a presymptomatic stage of AD [11], [12]. Although the time course

Therapeutic approaches that decrease Aβ synthesis

Attempts to decrease Aβ production involve inhibition of two secretase enzymes responsible for cleavage of Aβ from its much larger APP (Fig. 6) [59]. β-Secretase or β-amyloid cleaving enzyme (BACE) cleaves the N-terminus of Aβ, and the γ-secretase enzyme complex cleaves the C-terminus [60]. Studies of transgenic mice with deposit Aβ plaques in their brain have shown that γ-secretase inhibitors can prevent Aβ deposition [61]. Both β-secretase and γ-secretase have been proven to be difficult drug

Therapeutic approaches that increase Aβ clearance or decrease toxicity

Another anti-amyloid approach makes use of immunotherapy against Aβ. It is generally regarded that this approach lowers Aβ levels by augmenting clearance of Aβ. Schenk et al. [40] first demonstrated that active immunization of Aβ-depositing transgenic mice with Aβ peptides leads to circulating anti-Aβ antibodies and prevention of Aβ deposition in PDAPP mice. One possible mechanism for immunotherapy-induced Aβ clearance is the enhancement of microglial phagocytosis via Fc receptors [57]. Bard et

Human anti-amyloid therapy clinical trials

The first iteration of the immunotherapeutic approach in clinical trials involved active immunization with Aβ42 itself, along with an immunogenic adjuvant (QS-21). Unfortunately, this AN-1792 trial was suspended as a result of a 6% incidence of a serious adverse event of meningoencephalitis [58], [84] that may be related to the presence of cerebral amyloid angiopathy [85]. A report on a subset of patients suggested that successful immunization to Aβ slows cognitive decline [86], but the results

Conclusions

The potential applications of Aβ imaging agents include their use as diagnostic agents to detect cerebral β-amyloidosis, to help test the amyloid cascade hypothesis of AD and to assist with the development of anti-amyloid therapeutic drugs. While efforts are underway currently in all three areas of research, the most immediate impact of this class of imaging agents will likely be to aid in the in vivo evaluation of new anti-amyloid therapies. The clinical efficacy of these anti-amyloid

Acknowledgments

This work was supported by the National Institutes of Health through Grant Nos. R01 AG018402, P50 AG005133, R01 AG020226, R37 AG025516 and P01 AG025204 and the Alzheimer's Association through Grant No. TLL-01-3381.

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      Based on its structure and the analyses presented elsewhere (O'Hagan and Kell, 2015; O'Hagan and Kell, 2016; O'Hagan et al., 2015), the three Recon 2(.2) metabolites (Swainston et al., 2013, 2016; Thiele et al., 2013) and marketed drugs to which it is most similar are given in Fig 8.) However, while its 11C-derivative has been widely used in PET imaging of fibrils (e.g. (Driscoll et al., 2012; Grimmer et al., 2009; Mathis et al., 2007; Murray et al., 2015; Resnick et al., 2010; Wu et al., 2011)), PIB lacks the large optical absorbance shift and fluorescence enhancement characteristic of ThS and ThT (Wu et al., 2011). Other amyloid-selective dyes that have been used include X-34 (Excitation 400nm/Emission 455 nm), which is in fact a fluorescent derivative of CR (Ikonomovic et al., 2006; Link et al., 2001; Styren et al., 2000), chrysamine G (Kang and Han, 2001; Klunk et al., 1994) (Fig 6) (which is excited at 386 nm) and ANCA (excitation 380–430, emission 525–550).

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    ☆

    GE Healthcare holds a license agreement with the University of Pittsburgh based on the [11C]PiB imaging technology described in this article but provided no financial support for the preparation of this article and had no role in the writing or interpretation of the information contained in this article. Drs. Mathis and Klunk are co-inventors of [11C]PiB and, as such, have a financial interest in this license agreement.

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