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β-amyloid PET neuroimaging: A review of radiopharmaceutical development
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General Review
b-amyloid PET neuroimaging: A review of radiopharmaceutical development Neuro-imagerie TEP des plaques b-amyloides : une revue du développement des médicaments radiopharmaceutiques A.-C. Dupont *, M.-J. Santiago Ribeiro, D. Guilloteau, N. Arlicot Inserm U930, Inserm CIC-IT 1415, université François-Rabelais de Tours, CHRU de Tours, 2, boulevard Tonnellé, 37044 Tours cedex, France Received 2 December 2016; accepted 16 December 2016
Abstract Alzheimer’s disease (AD) is a neurodegenerative disease characterized by deposition of amyloid-b plaques that occurs even before symptoms of brain failure are clinically detectable. Whereas previously the diagnosis of AD was only routinely based on clinical assessment, an improvement over the past few years in imaging biomarkers has now led to reconsider the core of the AD diagnostic pathway. Therefore, positron emission tomography (PET) radiotracers for the in vivo imaging of amyloid plaques have been the focus of intense research. Many chemical compounds, mostly derived from the chemistry of amyloid histological staining dyes, have permitted to obtain promising brain amyloid radiopharmaceuticals. Three of them have been approved by the FDA and European regulatory bodies. The present review focuses on the development of these compounds not only as a suitable imaging biomarker to improve AD diagnosis, but also to evaluate new potential therapy. # 2016 Elsevier Masson SAS. All rights reserved. Keywords: Radiopharmaceutical; PET; Amyloid; Neuroimaging; Alzheimer’s disease
Résumé La maladie d’Alzheimer est une maladie neurodégénérative caractérisée par des dépôts protéiques anormaux, appelés plaques b-amyloïdes, qui apparaissent avant même les premiers symptômes cliniques de la maladie. Alors qu’historiquement, le diagnostic de la maladie est basé sur la seule évaluation clinique (éventuellement complété par de l’histologie pour un diagnostic de certitude), l’émergence de nouveaux biomarqueurs d’imagerie a permis de reconsidérer la prise en charge diagnostique de la maladie d’Alzheimer. Ainsi, de nombreux radiopharmaceutiques TEP pour visualiser in vivo les plaques b-amyloïdes ont été développés depuis une quinzaine d’années. Plusieurs familles chimiques, principalement dérivées de colorants organiques de l’amyloïdose en histologie, ont permis d’aboutir à ces radiopharmaceutiques d’intérêt pour l’imagerie amyloïde cérébrale. Trois de ces composés ont obtenu les autorisations américaines (FDA) et européennes (EMA). Cette revue porte donc sur le développement des radiopharmaceutiques présentant un intérêt dans le diagnostic précoce de la maladie d’Alzheimer mais aussi en tant que biomarqueur d’évaluation des thérapies émergentes. # 2016 Elsevier Masson SAS. Tous droits réservés. Mots clés : Médicament radiopharmaceutique ; TEP ; Amyloide ; Neuroimagerie ; Maladie d’Alzheimer
* Corresponding author. E-mail address: [email protected] (A.C. Dupont). http://dx.doi.org/10.1016/j.mednuc.2016.12.002 0928-1258/# 2016 Elsevier Masson SAS. All rights reserved.
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1. Introduction Alzheimer’s disease (AD) is the most common form of dementia that was first described by Alois Alzheimer in 1907 [1]. The clinical features of this chronic neurodegenerative disease include amnesic memory impairment, language deterioration, as well as functional and behavioural changes due to cognitive impairment. As the symptoms of Alzheimer’s disease progress slowly, the clinical diagnosis of AD is challenging and often late. The initial diagnosis is made by clinical evaluation assessing cognitive, language, and functional abilities based on criteria commonly referred to as the ‘‘National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association’’ (NINCDS/ADRDA). These criteria have been used for almost 30 years and provide a sensitivity of 81% and a specificity of 70% [2,3]. Although the diagnosis of probable and possible AD can be established clinically with the NINCDS-ADRDA criteria, a definite diagnosis requires postmortem histopathological confirmation. Although the precise molecular mechanisms that cause AD remain unknown, the amyloid cascade hypothesis, that senile plaques (SPs) play an important role in its development, is now widely accepted. In fact, post-mortem brains of AD patients have revealed the presence of extracellular SPs (aggregates of amyloid-b [Ab] protein) and intracellular neurofibrillary tangles (NFTs) composed of phosphorylated tau protein [4]. To date, the ‘‘gold standard’’ diagnosis for AD continues to be post-mortem histopathological staining studies using amyloid dyes such as thioflavin-S, thioflavin-T, and Congo red (Fig. 1A, B, C). Over the past two decades, the traditional view of AD as a purely clinical entity has changed to one of AD as a clinicalbiological entity. Subsequently, it has become increasingly possible to identify in vivo evidence of the specific neuropathology of AD by the use of validated and specific biomarkers. Among these, in vivo neuroimaging biomarkers, being highly correlated with the neuropathological AD lesions, have been introduced into the core diagnostic pathway. Neuroimaging and molecular imaging, in particular positron emission tomography (PET) are sensitive techniques able to identifying subtle molecular changes in the brain, even before structural changes are present. Namely, the accumulation of Ab protein has been reported to begin many years before the onset of detectable cognitive symptoms, establishing a window of opportunity for early diagnosis [5]. In this context, amyloid PET neuroimaging
has shown promise for the early diagnosis of AD. The development of PET radiotracers for the in vivo imaging of amyloid-b plaques has been the focus of intense research efforts in the past few years. More recently, amyloid-b neuroimaging seems to be even more important with the new therapeutic strategies emerging aimed at reducing Ab protein in the brain. This article retraces the history of the development of PET neuroimaging radiopharmaceuticals labeled with fluorine 18 (18F) or carbon 11 (11C) designed to bind in vivo to Ab plaques and their current regulatory status. 2. Ab radiopharmaceutical development In order to be a promising brain Ab imaging PET radiopharmaceutical, candidates must fulfill certain requirements. Mainly, three factors (i.e., lipophilicity, molecular weight, and affinity) determine the in vivo characteristics of a brain radiotracer able to cross the blood-brain barrier (BBB). Many other factors must be considered such as the rapid labeling of the precursor, appropriate clearance from a specific binding compartment and the negligible influence of potential labeled lipophilic metabolites [6]. In addition to having appropriate chemical and physical characteristics, a useful brain radioligand for Ab PET imaging must bind to amyloid plaques with a high affinity in vivo. 2.1. [18F]-FDDNP: historically the first Ab radiopharmaceutical The first PET radiotracer developed to image amyloid in vivo was the 2-(1-{6-[(2-[fluorine- 18]fluoroethyl)(methyl)amino]2-naphthyl}-ethylidene)malononitrile ([18F]FDDNP), (Fig. 2) a lipophilic naproxen derivative [7]. Barrio et al. (at UCLA), in 1999, showed that [18F]FDDNP PET detects pathology progression in Alzheimer’s disease and was able to distinguish the three groups of subject controls, mild cognitive impairment (MCI) and AD patients. In 2009, [18F]FDDNP was reported to be able to bind non-selectively to both Ab plaques and NFTs [8] assuming a lack of specificity and limiting its ability to differentiate AD from other taupathies [9]. [18F]-FDDNP is therefore not specific to Ab plaques in AD and its clinical use has been expanded to other cerebral pathologies with abnormal deposits of protein such as cerebral amyloid angiopathy, Pick’s disease, Parkinson’s disease, progressive supranuclear palsy or dementia with Lewy bodies [10]. Its clinical use seems to have
Fig. 1. Chemical structure of thioflavin-S (A), thioflavin-T (B), Congo Red (C). Structures chimiques de la thioflavine-S (A), de la thioflavin-T (B) et du rouge Congo (C).
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Fig. 2. Chemical structure of [18F]-FDDNP. Structure chimique du [18F]-FDDNP.
been compromised all the more so as [18F]FDDNP is rapidly metabolized in vivo with labelled metabolites able to cross the BBB thus increasing the nonspecific background signal and producing a low signal to noise ratio [11]. 2.2. First generation of radiopharmaceuticals: ‘‘[11C]-PIB period’’ After the limited success of [18F]-FDDNP, research has been focused on the pharmacomodulation of the histological dyes, known to bind to amyloid plaques in vitro. After years of research on Congo red derivatives, investigations turned at the end of the 1990’s to other pharmacophores. Thioflavin-T is a small molecule used for in vitro amyloid plaque histological examination. Numerous thioflavin-T derivatives (benzothiazole-aniline derivatives or BTA derivatives) have been synthetized. In vitro binding studies have shown that 6-OHBTA-1 binds specifically to insoluble amyloid fibrils with a low affinity for NFTs [12]. This compound differs from thioflavin-T due to the lack of three methyl groups which increase the lipophilicity. The carbon compound [11C]-6-OH-BTA-1 has displayed a good correlation between amyloid plaque distribution compared pathology [13]. In this way, thioflavinT has been used as the pharmacophore for the development of the most widely utilized and the most well-characterized PET imaging agent for the Ab plaques in the brain, the renowned [11C]-6-OH-BTA-1 and [11C]-PIB ([11C]2-(4-methylaminophenyl)- 6-hydroxybenzothiazole (Pittsburgh compound B) [14,15] (Fig. 3) by the Uppsala university in Sweden honoring the Pittsburgh university which had been synthetized previously. Studies have shown that [11C]-PIB retention in areas known to have high amyloid deposition was elevated in brains of AD patients compared to healthy controls [16]. Tolboom et al. [17] directly compared [11C]-PIB and [18F]-FDDNP in patients with AD, MCI and healthy controls. Visual analyses of the PET images confirmed the high cortical [11C]-PIB binding in AD, with predominantly white matter uptake in controls. High level of [18F]-FDDNP binding in subcortical structures suggests nonspecific binding (Fig. 4). Subsequently, it was shown that significant [11C]-PIB retention in 60% of MCI
Fig. 3. Chemical structure of [11C]-PIB. Structure chimique du [11C]-PIB.
Fig. 4. 11C-PIB (A) and 18F-FDDNP (B) BPND images in healthy control (left) and AD patient (right). High level of 18F-FDDNP binding in subcortical structure suggests nonspecific binding. Images (BDND) du 11C-PIB (A) et du 18F-FDDNP (B) chez un sujet contrôle (gauche) et un sujet atteint de la maladie d’Alzheimer (droite). Une forte fixation subcorticale du 18F-FDDNP suggère une forte liaison non spécifique. Reprinted from Tolboom et al. [18].
subjects; ratio spanning between AD patients (90%) and normal elderly (25%) [18,19]. This high retention in control subjects, not clinically mentally ill, is a major drawback for a routine clinical use. Furthermore, the short-life of carbon 11 which is about 20 minutes limits its use in clinical routine requiring a cyclotron at the site of injection. This limitation has led to the development of numerous Ab tracers labelled with fluorine 18 (half-time of 110 minutes) for more wide-spread availability and routine clinical use. 2.3. Second generation: [18F]-bamyloid radiopharmaceuticals This approach has yielded three main radiotracers, the 30 fluoro derivative of PIB (flutemetamol, Fig. 5) and stilbene derivatives florbetapir (Fig. 6) and florbetaben (Fig. 7). To date, these three compounds have been approved for clinical use by the Food and Drug Administration (FDA) and European regulatory authorities known under the name Vizamyl1, Amyvid1 and Neuraceq1 respectively. All of these derivatives
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Fig. 7. Chemical structure of [18F]-florbetaben. Structure chimique du [18F]-florbetaben. Fig. 5. Chemical structure of [18F]-flutemetamol. Structure chimique du [18F]-flutemetamol.
bind selectively with high affinity to fibrillar Ab and do not bind well to NFTs. 2.3.1. [18F]-Florbetapir (AmyvidTM) Styrylpyridine is a rigid core which provides a fundamental structural basis for developing new specific amyloid agents [20]. [18F]-Florbetapir is a stilbene derivative designed by Kung et al. [21] and developed by Avid Radiopharmaceuticals. [18F]-Florbetapir is a moderate lipophilicity molecule which contains an excellent specific affinity for amyloid plaques (Kd = 3.1 nM). It was initially observed during in vivo preclinical studies in monkeys as an appropriate pharmacokinetic after BBB entrance and an effective washout required for a clinical use [22]. Correlation evaluation between amyloid observation by PET and amyloid cortical burden is based on two main phase III clinical trials with one conducted by Avid Radiopharmaceuticals which demonstrated that [18F]-Florbetapir has a 92% sensitivity and a 100% specificity for the detection of Ab pathology [23]. Time activity curves revealed by Wong et al. [24] have shown the rapid reversible binding to Ab plaques allowing PET acquisition 30 minutes after injection. A second clinical trial, carried out by three PET centers in France, has studied the feasibility of using [18F]Florbetapir-PET in a clinical context [25] (Fig. 8). [18F]Florbetapir became the first fluorine 18 PET tracer approved by the FDA (2012) and the European Medicines Agency (EMA 2013) for clinical use in order to assess amyloid neuritic plaque density in adult patients with cognitive impairment (AD or other cognitive decline).
to AD after 2 years [28]. Many other preclinical and clinical studies conducted in parallel have shown [18F]-Florbetaben safety, tolerance, adapted pharmacokinetic and dosimetry for its clinical use [29]. Subsequently, [18F]-Florbetaben was approved by US and European authorities in 2014. 2.3.3. [18F]-Flutemetamol (VizamylTM) The successful use of [11C]-PIB for Ab neuroimaging led efforts to develop a fluorine 18 tracer that would be comparable. Then, a 30 -fluoro analogue of [11C]-PIB, [18F]-Flutemetamol was developed by GE Healthcare. This another second generation Ab tracer that can robustly differentiate AD and healthy controls [30,31] as well as predict disease progression in MCI subjects [32]. Some [18F]-Flutemetamol polar metabolites have been observed but are not able to cross
2.3.2. [18F]-Florbetaben (NeuraceqTM) [18F]-Florbetaben is also a stilbene derivative with high in vitro affinity and specificity for Ab fibrils synthetized by Kung et al. [26] and developed by Bayer Healthcare. The first-inhuman study assessing florbetaben in AD patients was carried out by Rowe et al. in 2008 [27]: AD patients, healthy controls and FLTD (Frontolateral temporal Dementia) are discriminated with high affinity and specificity (SUVR 2.0 0.3 vs 1.3 0.2; P < 0.0001). In MCI patients, [18F]-Florbetaben retention showed a predictive accuracy of 83% for conversion
Fig. 6. Chemical structure of [18F]-florbetapir. Structure chimique du [18F]-florbetapir.
Fig. 8. Representative axial, sagittal and coronal florbetapir-negative images of a HC subject (a) and a MCI patient (b), and florbetapir-positive images of a MCI patient (c) and an AD patient (d). Images négatives en coupes axiale, sagittale et coronale du florbetapir chez un sujet sain (a) et chez un patient MCI (troubles cognitifs légers) (b) ; et images positives du florbetapir chez un patient MCI (c) et chez un patient atteint de la maladie d’Alzheimer (d). Reprinted from: Camus, Eur J Nucl Med Mol Imaging, 2012 [25].
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through the BBB so they cannot be in competition with the radiotracer in the brain. While the cortical retention of [18F]Flutemetamol is similar to that of [11C]-PIB, the nonspecific retention in white matter is much higher [31]. [18F]Flutemetamol received FDA and EMA approval in 2013 and 2014 respectively.
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Fig. 10. Chemical structure of [18F]-AZD4694. Structure chimique du [18F]-AZD4694.
2.4. Third generation radiopharmaceuticals There is substantial evidence which shows that second generation fluorinated tracers are safe, well tolerated with favorable pharmacokinetics and radiation exposure. All tracers described above have been shown to robustly and reliably label brain amyloid plaques. The three 18F-radiopharmaceuticals approved by authorities have shown their capacity to distinguish AD patients and healthy controls but each tracer has slightly different characteristics such as the cortical and the white-matter retention that influence quantification. [18F]Florbetapir and [18F]-Florbetaben have a lower cortical grey matter retention than [11C]-PIB [33,34] that can be visually misinterpreted as relatively higher for nonspecific binding to white matter. In contrast [18F]-Flutemetamol has a real nonspecific white matter retention which is higher than [11C]-PIB [31]. Due to this lower signal-noise ratio, care in visual interpretation of amyloid positive versus amyloid negative regions should be taken into account, particularly in the case of [18F]-Flutemetamol when considering cortical vs. white-matter retention [35]. Therefore, future amyloid PET radiopharmaceuticals will have to outperform the leaders particularly in the nonspecific binding field. 2.4.1. [11C]-AZD2184 Astra-Zeneca has proposed the 2-(6-[11C]-methylaminopyridine-3-yl)benzothiazol-6-ol ([11C]-AZD2184, Fig. 9), a structural analogue of PIB where the 2-phenyl substituent has been replaced by pyridine moiety. This substitution lowers the lipophilicity compared with [11C]-PIB and may decrease the nonspecific binding to the white-matter retention. Preliminary studies have confirmed that the AZD2184 radiolabeled with 3H bounded to Ab with high affinity and a lower nonspecific binding in autoradiographic studies compared to [3H]-PIB [36]. Despite its very low nonspecific binding to white matter, [11C]AZD2184 similarly to [11C]-PIB, is not considered appropriate for a use in clinical centers. 2.4.2. [18F]-AZD4694 In order to counteract the short half-time of 11C, AstraZeneca has developed a fluorine analog, the 2-(2-[18F]fluoro-6methylaminopyridine-3-yl)benzothiazol-5-ol ([18F]-AZD4694,
Fig. 9. Chemical structure of [11C]-AZD2184. Structure chimique du [11C]-AZD2184.
(Fig. 10). Initial clinical validation studies have demonstrated that [18F]-AZD4694 has a low nonspecific binding to white matter and an excellent correlation with [11C]-PIB cortical retention. Schou et al. [37] have reported in nonhuman primates that [11C]-AZD4694 has displayed slightly lower nonspecific binding in white matter than [11C]-PIB as well as more rapid pharmacokinetics in the brain (Fig. 11). In the clinical study conducted by Cselenyi et al. [38], [18F]-AZD4694 has shown a robust distinction between AD patients and heathy controls. With these preliminary data [18F]-AZD4694 could be envisaged in clinical use with a better signal-noise ratio than previous compounds. Despite a large number of PET radiopharmaceuticals for the non-invasive imaging of Ab plaque burden availability, research projects allow new tracer development such as the ongoing development of the [11C]-TAZA by Pan et al. [39]. 3. Discussion 3.1. Clinical use of amyloid-PET imaging AD is a leading cause of dementia with symptoms including progressive memory loss and cognitive decline. As the general population continues to age rapidly all over the world, the increase in the number of AD patients constitutes a serious social issue. The clinical diagnosis of AD is primarily based on patient history, physical examination and cognitive assessment but the main difficulty in achieving accurate clinical diagnoses may arise because common dementing diseases, such as vascular dementia, dementia with Lewy bodies, frontotemporal dementia and others, share many symptoms with AD. This AD definition as a type of dementia has been based on clinical criteria proposed in 1984 (NINCDS-ADRDA) but have evolved over the years in order to conform to biological, scientific and technological advances improving the diagnosis. Clinical diagnostic criteria for AD were up-to-dated in 2007, to incorporate new advances including biomarkers and to help physicians better define the full spectrum of AD [40,41]. This change has enabled AD diagnosis to be extended into the prodromal stage, where the disease can be diagnosed with supportive biomarkers. Then, in 2014, the International Working Group (IWG presented evidence for refining the biomarker criteria [42]. Since then, cerebrospinal fluid biomarkers (CSF) (Ab1-42; T-tau or P-tau) and amyloid PET have shown to be well correlated with the AD physiopathology, and considered the most specific biomarkers for a diagnosis of AD at any point in the disease continuum. It is noteworthy that
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Fig. 11. Fused MRI and color coded PET images showing distribution of radioactivity in a monkey brain following intravenous injection of [11C]AZD4694 (upper panel) and [11C]PiB (lower panel). Summation images from 9 to 93 min are shown. Image intensity corrected for injected radioactivity. Via a simple visual inspection, the PET images indicate that [11C]AZD4694 has lower nonspecific binding in the brain compared to [11C]PiB. Images fusionnées IRM/TEP montrant la distribution cérébrale de la radioactivité chez un singe après l’injection du [11C]AZD4694 (haut) et du [11C]PiB (bas). Visuellement, les images TEP montrent que l’[11C]AZD4694 présente une plus faible liaison non-spécifique que le [11C]PiB. Reprinted from Schou et al.
topographical markers of brain regional structural and metabolic changes (volumetric MRI and FDG-PET) have been downgraded due to a lack of pathological specificity. Thus, as the criteria for the diagnosis of AD have evolved, Ab imaging PET has earned an increasingly important role in clinical practice. In the same paper, the expert group has proposed a revision for typical AD diagnosis: ‘‘A research diagnosis of typical AD can be made in the presence of an amnesic syndrome of the hippocampal type that can be associated with various cognitive or behavioural changes, and at least one of the following changes indicative of in vivo Alzheimer’s pathology: a CSF profile consisting of decreased Ab1-42 levers together with increased T-tau or P-tau concentrations, or an increased retention on amyloid PET tracer’’. Because of a high level of patient and professional interest, amyloid PET has the potential to be widely used and that is why research had rushed to develop plenty of amyloid radiopharmaceuticals. In this article, a non-exhaustive overview of compounds, developed for amyloid PET imaging, is presented in their chronologic sequence of development. In the last 15 years several carbon 11 and fluorine 18 labeled radiotracers have been developed as potential amyloid imaging biomarkers. The chemical backbones for developing amyloid radioligands derived from the chemistry of histological staining dyes belong to four different categories and include aminonapthalenes, benzothiazoles, stilbenes, and imidazopyridines. The University of California reported the first in vivo radiopharmaceutical of amyloid plaques in humans derived on a highly lipophilic fluorescent
probe, 2-{1-[6-(dimethylamino)-2-naphthyl]ethylidene} malononitrile (DDNP). Unfortunately, the radiofluorinated tracer [18F]FDDNP presented a high nonspecific binding and binded to NFTs in the postmortem AD brain. At the same time, Mathis et al., from the University of Pittsburgh Medical Center developed several lipophilic thioflavin-T analogs. Among these the [11C]PiB is the most studied Ab PET radiopharmaceutical in the world. Because 11C is not ideal for commercialization, longer-lived 18F-labeled Ab-selective radiopharmaceuticals have emerged. To date, three such compounds have been approved for clinical use by the US and European regulatory authorities, including 18F-Florbetapir, 18F-Florbetaben and 18F-Flutemetamol. In comparison to [11C]PiB, all three tracers have shown higher nonspecific white matter uptake. 18F-Florbetapir and 18 F-Florbetaben are two structurally fluoro-pegylated stilbene derivative with excellent binding affinity for Ab while chemically 18F-Flutemetamol corresponds to [18F]30 -FPIB (Fig. 12). As these radiopharmaceuticals with their strengths and weaknesses enter into clinical use, it is important that practitioners are aware of the potential diagnostic benefits and limitations of amyloid PET. In practice, negative amyloid PET scan is inconsistent with an AD diagnosis suggesting the need for further diagnosis investigation. Furthermore, in MCI patients, there is emerging evidence that a negative amyloid PET scan indicates lower probability of clinically significant cognitive worsening for at least the next 36 months [43].
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Fig. 12. AD diagnostic criteria evolution with amyloid radiopharmaceutical development. Evolution des critères diagnostiques de la maladie d’Alzheimer et développement des médicaments radiopharmaceutiques spécifiques de la protéine amyloïde.
3.2. Amyloid-PET imaging to assess the efficacy of antiamyloid therapy
Disclosure of interest The authors declare that they have no competing interest.
Currently approved drug treatments for AD can restrain the symptoms, but no proven treatments stop the progression of AD or delay or prevent the onset of AD. Several clinical studies assessing new AD therapies have used amyloid PET imaging as an outcome measure. Two trials testing phenserine and solanezumab [44] in AD and/or MCI patients have used [18F]-Florbetapir but no impact of therapies on brain amyloid PET was highlight. In contrast, in trials using monoclonal antibodies like bapineuzumab or gantenerumab [45,46], small to modest treatment reductions on brain amyloid by PET were observed. Ab imaging could therefore play a significant role in identifying patients at risk for AD who would be suitable candidates for anti-Ab therapies. In addition, Ab imaging might have a significant role in monitoring the efficacy of anti-Ab therapies. 4. Conclusion A prospective study [47] found that patients often showed reduced levels of anxiety after diagnosis of a dementing condition. By documenting the absence or presence of neuropathology, an amyloid PET scan may provide valuable knowledge to both patients and family members [48]. Until recently, visualization of b-amyloid plaque burden as a key element for diagnosing AD was only possible at autopsy. Our understanding of the pathophysiological mechanisms of AD has been significantly enhanced through the PET amyloid neuroimaging. Currently, amyloid-PET neuroimaging has been a useful tool to estimate b-amyloid plaques during its life. Three radiopharmaceuticals have been approved by the EMA, unfortunately, its use in the nuclear medicine departments in France has remained limited due to the lack of individual community approval.
Acknowledgments This study was supported by the French National Agency for Research (‘‘Investissements d’Avenir’’ no. ANR-11-LABX0018-01), IRON; and the European Union’s Seventh Framework Programme (FP7/2004-2013) under grant agreement no. 278850 (INMiND). References [1] Stelzmann RA, Norman Schnitzlein H, Reed Murtagh F. An english translation of alzheimer’s 1907 paper ‘‘über eine eigenartige erkankung der hirnrinde?’’ Clin Anat 1995;8:429–31. [2] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–44. [3] Knopman DS, DeKosky ST, Cummings JL, Chui H, Corey-Bloom J, Relkin N, et al. Practice parameter: diagnosis of dementia (an evidencebased review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1143–53. [4] Hyman BT, Trojanowski JQ. Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 1997;56:1095–7. [5] Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 2012;367:795–804. [6] Davis KL, Charney D, Coyle JT, Nemeroff C. The fifth generation of progress. American College of Neuropsychopharmacology; 2002. [7] Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, et al. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer’s disease. J Neurosci 2001;21:RC189.
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b-amyloid PET neuroimaging: A review of radiopharmaceutical development Neuro-imagerie TEP des plaques b-amyloides : une revue du développement des médicaments radiopharmaceutiques A.-C. Dupont *, M.-J. Santiago Ribeiro, D. Guilloteau, N. Arlicot Inserm U930, Inserm CIC-IT 1415, université François-Rabelais de Tours, CHRU de Tours, 2, boulevard Tonnellé, 37044 Tours cedex, France Received 2 December 2016; accepted 16 December 2016
Abstract Alzheimer’s disease (AD) is a neurodegenerative disease characterized by deposition of amyloid-b plaques that occurs even before symptoms of brain failure are clinically detectable. Whereas previously the diagnosis of AD was only routinely based on clinical assessment, an improvement over the past few years in imaging biomarkers has now led to reconsider the core of the AD diagnostic pathway. Therefore, positron emission tomography (PET) radiotracers for the in vivo imaging of amyloid plaques have been the focus of intense research. Many chemical compounds, mostly derived from the chemistry of amyloid histological staining dyes, have permitted to obtain promising brain amyloid radiopharmaceuticals. Three of them have been approved by the FDA and European regulatory bodies. The present review focuses on the development of these compounds not only as a suitable imaging biomarker to improve AD diagnosis, but also to evaluate new potential therapy. # 2016 Elsevier Masson SAS. All rights reserved. Keywords: Radiopharmaceutical; PET; Amyloid; Neuroimaging; Alzheimer’s disease
Résumé La maladie d’Alzheimer est une maladie neurodégénérative caractérisée par des dépôts protéiques anormaux, appelés plaques b-amyloïdes, qui apparaissent avant même les premiers symptômes cliniques de la maladie. Alors qu’historiquement, le diagnostic de la maladie est basé sur la seule évaluation clinique (éventuellement complété par de l’histologie pour un diagnostic de certitude), l’émergence de nouveaux biomarqueurs d’imagerie a permis de reconsidérer la prise en charge diagnostique de la maladie d’Alzheimer. Ainsi, de nombreux radiopharmaceutiques TEP pour visualiser in vivo les plaques b-amyloïdes ont été développés depuis une quinzaine d’années. Plusieurs familles chimiques, principalement dérivées de colorants organiques de l’amyloïdose en histologie, ont permis d’aboutir à ces radiopharmaceutiques d’intérêt pour l’imagerie amyloïde cérébrale. Trois de ces composés ont obtenu les autorisations américaines (FDA) et européennes (EMA). Cette revue porte donc sur le développement des radiopharmaceutiques présentant un intérêt dans le diagnostic précoce de la maladie d’Alzheimer mais aussi en tant que biomarqueur d’évaluation des thérapies émergentes. # 2016 Elsevier Masson SAS. Tous droits réservés. Mots clés : Médicament radiopharmaceutique ; TEP ; Amyloide ; Neuroimagerie ; Maladie d’Alzheimer
* Corresponding author. E-mail address: [email protected] (A.C. Dupont). http://dx.doi.org/10.1016/j.mednuc.2016.12.002 0928-1258/# 2016 Elsevier Masson SAS. All rights reserved.
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1. Introduction Alzheimer’s disease (AD) is the most common form of dementia that was first described by Alois Alzheimer in 1907 [1]. The clinical features of this chronic neurodegenerative disease include amnesic memory impairment, language deterioration, as well as functional and behavioural changes due to cognitive impairment. As the symptoms of Alzheimer’s disease progress slowly, the clinical diagnosis of AD is challenging and often late. The initial diagnosis is made by clinical evaluation assessing cognitive, language, and functional abilities based on criteria commonly referred to as the ‘‘National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association’’ (NINCDS/ADRDA). These criteria have been used for almost 30 years and provide a sensitivity of 81% and a specificity of 70% [2,3]. Although the diagnosis of probable and possible AD can be established clinically with the NINCDS-ADRDA criteria, a definite diagnosis requires postmortem histopathological confirmation. Although the precise molecular mechanisms that cause AD remain unknown, the amyloid cascade hypothesis, that senile plaques (SPs) play an important role in its development, is now widely accepted. In fact, post-mortem brains of AD patients have revealed the presence of extracellular SPs (aggregates of amyloid-b [Ab] protein) and intracellular neurofibrillary tangles (NFTs) composed of phosphorylated tau protein [4]. To date, the ‘‘gold standard’’ diagnosis for AD continues to be post-mortem histopathological staining studies using amyloid dyes such as thioflavin-S, thioflavin-T, and Congo red (Fig. 1A, B, C). Over the past two decades, the traditional view of AD as a purely clinical entity has changed to one of AD as a clinicalbiological entity. Subsequently, it has become increasingly possible to identify in vivo evidence of the specific neuropathology of AD by the use of validated and specific biomarkers. Among these, in vivo neuroimaging biomarkers, being highly correlated with the neuropathological AD lesions, have been introduced into the core diagnostic pathway. Neuroimaging and molecular imaging, in particular positron emission tomography (PET) are sensitive techniques able to identifying subtle molecular changes in the brain, even before structural changes are present. Namely, the accumulation of Ab protein has been reported to begin many years before the onset of detectable cognitive symptoms, establishing a window of opportunity for early diagnosis [5]. In this context, amyloid PET neuroimaging
has shown promise for the early diagnosis of AD. The development of PET radiotracers for the in vivo imaging of amyloid-b plaques has been the focus of intense research efforts in the past few years. More recently, amyloid-b neuroimaging seems to be even more important with the new therapeutic strategies emerging aimed at reducing Ab protein in the brain. This article retraces the history of the development of PET neuroimaging radiopharmaceuticals labeled with fluorine 18 (18F) or carbon 11 (11C) designed to bind in vivo to Ab plaques and their current regulatory status. 2. Ab radiopharmaceutical development In order to be a promising brain Ab imaging PET radiopharmaceutical, candidates must fulfill certain requirements. Mainly, three factors (i.e., lipophilicity, molecular weight, and affinity) determine the in vivo characteristics of a brain radiotracer able to cross the blood-brain barrier (BBB). Many other factors must be considered such as the rapid labeling of the precursor, appropriate clearance from a specific binding compartment and the negligible influence of potential labeled lipophilic metabolites [6]. In addition to having appropriate chemical and physical characteristics, a useful brain radioligand for Ab PET imaging must bind to amyloid plaques with a high affinity in vivo. 2.1. [18F]-FDDNP: historically the first Ab radiopharmaceutical The first PET radiotracer developed to image amyloid in vivo was the 2-(1-{6-[(2-[fluorine- 18]fluoroethyl)(methyl)amino]2-naphthyl}-ethylidene)malononitrile ([18F]FDDNP), (Fig. 2) a lipophilic naproxen derivative [7]. Barrio et al. (at UCLA), in 1999, showed that [18F]FDDNP PET detects pathology progression in Alzheimer’s disease and was able to distinguish the three groups of subject controls, mild cognitive impairment (MCI) and AD patients. In 2009, [18F]FDDNP was reported to be able to bind non-selectively to both Ab plaques and NFTs [8] assuming a lack of specificity and limiting its ability to differentiate AD from other taupathies [9]. [18F]-FDDNP is therefore not specific to Ab plaques in AD and its clinical use has been expanded to other cerebral pathologies with abnormal deposits of protein such as cerebral amyloid angiopathy, Pick’s disease, Parkinson’s disease, progressive supranuclear palsy or dementia with Lewy bodies [10]. Its clinical use seems to have
Fig. 1. Chemical structure of thioflavin-S (A), thioflavin-T (B), Congo Red (C). Structures chimiques de la thioflavine-S (A), de la thioflavin-T (B) et du rouge Congo (C).
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Fig. 2. Chemical structure of [18F]-FDDNP. Structure chimique du [18F]-FDDNP.
been compromised all the more so as [18F]FDDNP is rapidly metabolized in vivo with labelled metabolites able to cross the BBB thus increasing the nonspecific background signal and producing a low signal to noise ratio [11]. 2.2. First generation of radiopharmaceuticals: ‘‘[11C]-PIB period’’ After the limited success of [18F]-FDDNP, research has been focused on the pharmacomodulation of the histological dyes, known to bind to amyloid plaques in vitro. After years of research on Congo red derivatives, investigations turned at the end of the 1990’s to other pharmacophores. Thioflavin-T is a small molecule used for in vitro amyloid plaque histological examination. Numerous thioflavin-T derivatives (benzothiazole-aniline derivatives or BTA derivatives) have been synthetized. In vitro binding studies have shown that 6-OHBTA-1 binds specifically to insoluble amyloid fibrils with a low affinity for NFTs [12]. This compound differs from thioflavin-T due to the lack of three methyl groups which increase the lipophilicity. The carbon compound [11C]-6-OH-BTA-1 has displayed a good correlation between amyloid plaque distribution compared pathology [13]. In this way, thioflavinT has been used as the pharmacophore for the development of the most widely utilized and the most well-characterized PET imaging agent for the Ab plaques in the brain, the renowned [11C]-6-OH-BTA-1 and [11C]-PIB ([11C]2-(4-methylaminophenyl)- 6-hydroxybenzothiazole (Pittsburgh compound B) [14,15] (Fig. 3) by the Uppsala university in Sweden honoring the Pittsburgh university which had been synthetized previously. Studies have shown that [11C]-PIB retention in areas known to have high amyloid deposition was elevated in brains of AD patients compared to healthy controls [16]. Tolboom et al. [17] directly compared [11C]-PIB and [18F]-FDDNP in patients with AD, MCI and healthy controls. Visual analyses of the PET images confirmed the high cortical [11C]-PIB binding in AD, with predominantly white matter uptake in controls. High level of [18F]-FDDNP binding in subcortical structures suggests nonspecific binding (Fig. 4). Subsequently, it was shown that significant [11C]-PIB retention in 60% of MCI
Fig. 3. Chemical structure of [11C]-PIB. Structure chimique du [11C]-PIB.
Fig. 4. 11C-PIB (A) and 18F-FDDNP (B) BPND images in healthy control (left) and AD patient (right). High level of 18F-FDDNP binding in subcortical structure suggests nonspecific binding. Images (BDND) du 11C-PIB (A) et du 18F-FDDNP (B) chez un sujet contrôle (gauche) et un sujet atteint de la maladie d’Alzheimer (droite). Une forte fixation subcorticale du 18F-FDDNP suggère une forte liaison non spécifique. Reprinted from Tolboom et al. [18].
subjects; ratio spanning between AD patients (90%) and normal elderly (25%) [18,19]. This high retention in control subjects, not clinically mentally ill, is a major drawback for a routine clinical use. Furthermore, the short-life of carbon 11 which is about 20 minutes limits its use in clinical routine requiring a cyclotron at the site of injection. This limitation has led to the development of numerous Ab tracers labelled with fluorine 18 (half-time of 110 minutes) for more wide-spread availability and routine clinical use. 2.3. Second generation: [18F]-bamyloid radiopharmaceuticals This approach has yielded three main radiotracers, the 30 fluoro derivative of PIB (flutemetamol, Fig. 5) and stilbene derivatives florbetapir (Fig. 6) and florbetaben (Fig. 7). To date, these three compounds have been approved for clinical use by the Food and Drug Administration (FDA) and European regulatory authorities known under the name Vizamyl1, Amyvid1 and Neuraceq1 respectively. All of these derivatives
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Fig. 7. Chemical structure of [18F]-florbetaben. Structure chimique du [18F]-florbetaben. Fig. 5. Chemical structure of [18F]-flutemetamol. Structure chimique du [18F]-flutemetamol.
bind selectively with high affinity to fibrillar Ab and do not bind well to NFTs. 2.3.1. [18F]-Florbetapir (AmyvidTM) Styrylpyridine is a rigid core which provides a fundamental structural basis for developing new specific amyloid agents [20]. [18F]-Florbetapir is a stilbene derivative designed by Kung et al. [21] and developed by Avid Radiopharmaceuticals. [18F]-Florbetapir is a moderate lipophilicity molecule which contains an excellent specific affinity for amyloid plaques (Kd = 3.1 nM). It was initially observed during in vivo preclinical studies in monkeys as an appropriate pharmacokinetic after BBB entrance and an effective washout required for a clinical use [22]. Correlation evaluation between amyloid observation by PET and amyloid cortical burden is based on two main phase III clinical trials with one conducted by Avid Radiopharmaceuticals which demonstrated that [18F]-Florbetapir has a 92% sensitivity and a 100% specificity for the detection of Ab pathology [23]. Time activity curves revealed by Wong et al. [24] have shown the rapid reversible binding to Ab plaques allowing PET acquisition 30 minutes after injection. A second clinical trial, carried out by three PET centers in France, has studied the feasibility of using [18F]Florbetapir-PET in a clinical context [25] (Fig. 8). [18F]Florbetapir became the first fluorine 18 PET tracer approved by the FDA (2012) and the European Medicines Agency (EMA 2013) for clinical use in order to assess amyloid neuritic plaque density in adult patients with cognitive impairment (AD or other cognitive decline).
to AD after 2 years [28]. Many other preclinical and clinical studies conducted in parallel have shown [18F]-Florbetaben safety, tolerance, adapted pharmacokinetic and dosimetry for its clinical use [29]. Subsequently, [18F]-Florbetaben was approved by US and European authorities in 2014. 2.3.3. [18F]-Flutemetamol (VizamylTM) The successful use of [11C]-PIB for Ab neuroimaging led efforts to develop a fluorine 18 tracer that would be comparable. Then, a 30 -fluoro analogue of [11C]-PIB, [18F]-Flutemetamol was developed by GE Healthcare. This another second generation Ab tracer that can robustly differentiate AD and healthy controls [30,31] as well as predict disease progression in MCI subjects [32]. Some [18F]-Flutemetamol polar metabolites have been observed but are not able to cross
2.3.2. [18F]-Florbetaben (NeuraceqTM) [18F]-Florbetaben is also a stilbene derivative with high in vitro affinity and specificity for Ab fibrils synthetized by Kung et al. [26] and developed by Bayer Healthcare. The first-inhuman study assessing florbetaben in AD patients was carried out by Rowe et al. in 2008 [27]: AD patients, healthy controls and FLTD (Frontolateral temporal Dementia) are discriminated with high affinity and specificity (SUVR 2.0 0.3 vs 1.3 0.2; P < 0.0001). In MCI patients, [18F]-Florbetaben retention showed a predictive accuracy of 83% for conversion
Fig. 6. Chemical structure of [18F]-florbetapir. Structure chimique du [18F]-florbetapir.
Fig. 8. Representative axial, sagittal and coronal florbetapir-negative images of a HC subject (a) and a MCI patient (b), and florbetapir-positive images of a MCI patient (c) and an AD patient (d). Images négatives en coupes axiale, sagittale et coronale du florbetapir chez un sujet sain (a) et chez un patient MCI (troubles cognitifs légers) (b) ; et images positives du florbetapir chez un patient MCI (c) et chez un patient atteint de la maladie d’Alzheimer (d). Reprinted from: Camus, Eur J Nucl Med Mol Imaging, 2012 [25].
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through the BBB so they cannot be in competition with the radiotracer in the brain. While the cortical retention of [18F]Flutemetamol is similar to that of [11C]-PIB, the nonspecific retention in white matter is much higher [31]. [18F]Flutemetamol received FDA and EMA approval in 2013 and 2014 respectively.
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Fig. 10. Chemical structure of [18F]-AZD4694. Structure chimique du [18F]-AZD4694.
2.4. Third generation radiopharmaceuticals There is substantial evidence which shows that second generation fluorinated tracers are safe, well tolerated with favorable pharmacokinetics and radiation exposure. All tracers described above have been shown to robustly and reliably label brain amyloid plaques. The three 18F-radiopharmaceuticals approved by authorities have shown their capacity to distinguish AD patients and healthy controls but each tracer has slightly different characteristics such as the cortical and the white-matter retention that influence quantification. [18F]Florbetapir and [18F]-Florbetaben have a lower cortical grey matter retention than [11C]-PIB [33,34] that can be visually misinterpreted as relatively higher for nonspecific binding to white matter. In contrast [18F]-Flutemetamol has a real nonspecific white matter retention which is higher than [11C]-PIB [31]. Due to this lower signal-noise ratio, care in visual interpretation of amyloid positive versus amyloid negative regions should be taken into account, particularly in the case of [18F]-Flutemetamol when considering cortical vs. white-matter retention [35]. Therefore, future amyloid PET radiopharmaceuticals will have to outperform the leaders particularly in the nonspecific binding field. 2.4.1. [11C]-AZD2184 Astra-Zeneca has proposed the 2-(6-[11C]-methylaminopyridine-3-yl)benzothiazol-6-ol ([11C]-AZD2184, Fig. 9), a structural analogue of PIB where the 2-phenyl substituent has been replaced by pyridine moiety. This substitution lowers the lipophilicity compared with [11C]-PIB and may decrease the nonspecific binding to the white-matter retention. Preliminary studies have confirmed that the AZD2184 radiolabeled with 3H bounded to Ab with high affinity and a lower nonspecific binding in autoradiographic studies compared to [3H]-PIB [36]. Despite its very low nonspecific binding to white matter, [11C]AZD2184 similarly to [11C]-PIB, is not considered appropriate for a use in clinical centers. 2.4.2. [18F]-AZD4694 In order to counteract the short half-time of 11C, AstraZeneca has developed a fluorine analog, the 2-(2-[18F]fluoro-6methylaminopyridine-3-yl)benzothiazol-5-ol ([18F]-AZD4694,
Fig. 9. Chemical structure of [11C]-AZD2184. Structure chimique du [11C]-AZD2184.
(Fig. 10). Initial clinical validation studies have demonstrated that [18F]-AZD4694 has a low nonspecific binding to white matter and an excellent correlation with [11C]-PIB cortical retention. Schou et al. [37] have reported in nonhuman primates that [11C]-AZD4694 has displayed slightly lower nonspecific binding in white matter than [11C]-PIB as well as more rapid pharmacokinetics in the brain (Fig. 11). In the clinical study conducted by Cselenyi et al. [38], [18F]-AZD4694 has shown a robust distinction between AD patients and heathy controls. With these preliminary data [18F]-AZD4694 could be envisaged in clinical use with a better signal-noise ratio than previous compounds. Despite a large number of PET radiopharmaceuticals for the non-invasive imaging of Ab plaque burden availability, research projects allow new tracer development such as the ongoing development of the [11C]-TAZA by Pan et al. [39]. 3. Discussion 3.1. Clinical use of amyloid-PET imaging AD is a leading cause of dementia with symptoms including progressive memory loss and cognitive decline. As the general population continues to age rapidly all over the world, the increase in the number of AD patients constitutes a serious social issue. The clinical diagnosis of AD is primarily based on patient history, physical examination and cognitive assessment but the main difficulty in achieving accurate clinical diagnoses may arise because common dementing diseases, such as vascular dementia, dementia with Lewy bodies, frontotemporal dementia and others, share many symptoms with AD. This AD definition as a type of dementia has been based on clinical criteria proposed in 1984 (NINCDS-ADRDA) but have evolved over the years in order to conform to biological, scientific and technological advances improving the diagnosis. Clinical diagnostic criteria for AD were up-to-dated in 2007, to incorporate new advances including biomarkers and to help physicians better define the full spectrum of AD [40,41]. This change has enabled AD diagnosis to be extended into the prodromal stage, where the disease can be diagnosed with supportive biomarkers. Then, in 2014, the International Working Group (IWG presented evidence for refining the biomarker criteria [42]. Since then, cerebrospinal fluid biomarkers (CSF) (Ab1-42; T-tau or P-tau) and amyloid PET have shown to be well correlated with the AD physiopathology, and considered the most specific biomarkers for a diagnosis of AD at any point in the disease continuum. It is noteworthy that
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Fig. 11. Fused MRI and color coded PET images showing distribution of radioactivity in a monkey brain following intravenous injection of [11C]AZD4694 (upper panel) and [11C]PiB (lower panel). Summation images from 9 to 93 min are shown. Image intensity corrected for injected radioactivity. Via a simple visual inspection, the PET images indicate that [11C]AZD4694 has lower nonspecific binding in the brain compared to [11C]PiB. Images fusionnées IRM/TEP montrant la distribution cérébrale de la radioactivité chez un singe après l’injection du [11C]AZD4694 (haut) et du [11C]PiB (bas). Visuellement, les images TEP montrent que l’[11C]AZD4694 présente une plus faible liaison non-spécifique que le [11C]PiB. Reprinted from Schou et al.
topographical markers of brain regional structural and metabolic changes (volumetric MRI and FDG-PET) have been downgraded due to a lack of pathological specificity. Thus, as the criteria for the diagnosis of AD have evolved, Ab imaging PET has earned an increasingly important role in clinical practice. In the same paper, the expert group has proposed a revision for typical AD diagnosis: ‘‘A research diagnosis of typical AD can be made in the presence of an amnesic syndrome of the hippocampal type that can be associated with various cognitive or behavioural changes, and at least one of the following changes indicative of in vivo Alzheimer’s pathology: a CSF profile consisting of decreased Ab1-42 levers together with increased T-tau or P-tau concentrations, or an increased retention on amyloid PET tracer’’. Because of a high level of patient and professional interest, amyloid PET has the potential to be widely used and that is why research had rushed to develop plenty of amyloid radiopharmaceuticals. In this article, a non-exhaustive overview of compounds, developed for amyloid PET imaging, is presented in their chronologic sequence of development. In the last 15 years several carbon 11 and fluorine 18 labeled radiotracers have been developed as potential amyloid imaging biomarkers. The chemical backbones for developing amyloid radioligands derived from the chemistry of histological staining dyes belong to four different categories and include aminonapthalenes, benzothiazoles, stilbenes, and imidazopyridines. The University of California reported the first in vivo radiopharmaceutical of amyloid plaques in humans derived on a highly lipophilic fluorescent
probe, 2-{1-[6-(dimethylamino)-2-naphthyl]ethylidene} malononitrile (DDNP). Unfortunately, the radiofluorinated tracer [18F]FDDNP presented a high nonspecific binding and binded to NFTs in the postmortem AD brain. At the same time, Mathis et al., from the University of Pittsburgh Medical Center developed several lipophilic thioflavin-T analogs. Among these the [11C]PiB is the most studied Ab PET radiopharmaceutical in the world. Because 11C is not ideal for commercialization, longer-lived 18F-labeled Ab-selective radiopharmaceuticals have emerged. To date, three such compounds have been approved for clinical use by the US and European regulatory authorities, including 18F-Florbetapir, 18F-Florbetaben and 18F-Flutemetamol. In comparison to [11C]PiB, all three tracers have shown higher nonspecific white matter uptake. 18F-Florbetapir and 18 F-Florbetaben are two structurally fluoro-pegylated stilbene derivative with excellent binding affinity for Ab while chemically 18F-Flutemetamol corresponds to [18F]30 -FPIB (Fig. 12). As these radiopharmaceuticals with their strengths and weaknesses enter into clinical use, it is important that practitioners are aware of the potential diagnostic benefits and limitations of amyloid PET. In practice, negative amyloid PET scan is inconsistent with an AD diagnosis suggesting the need for further diagnosis investigation. Furthermore, in MCI patients, there is emerging evidence that a negative amyloid PET scan indicates lower probability of clinically significant cognitive worsening for at least the next 36 months [43].
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Fig. 12. AD diagnostic criteria evolution with amyloid radiopharmaceutical development. Evolution des critères diagnostiques de la maladie d’Alzheimer et développement des médicaments radiopharmaceutiques spécifiques de la protéine amyloïde.
3.2. Amyloid-PET imaging to assess the efficacy of antiamyloid therapy
Disclosure of interest The authors declare that they have no competing interest.
Currently approved drug treatments for AD can restrain the symptoms, but no proven treatments stop the progression of AD or delay or prevent the onset of AD. Several clinical studies assessing new AD therapies have used amyloid PET imaging as an outcome measure. Two trials testing phenserine and solanezumab [44] in AD and/or MCI patients have used [18F]-Florbetapir but no impact of therapies on brain amyloid PET was highlight. In contrast, in trials using monoclonal antibodies like bapineuzumab or gantenerumab [45,46], small to modest treatment reductions on brain amyloid by PET were observed. Ab imaging could therefore play a significant role in identifying patients at risk for AD who would be suitable candidates for anti-Ab therapies. In addition, Ab imaging might have a significant role in monitoring the efficacy of anti-Ab therapies. 4. Conclusion A prospective study [47] found that patients often showed reduced levels of anxiety after diagnosis of a dementing condition. By documenting the absence or presence of neuropathology, an amyloid PET scan may provide valuable knowledge to both patients and family members [48]. Until recently, visualization of b-amyloid plaque burden as a key element for diagnosing AD was only possible at autopsy. Our understanding of the pathophysiological mechanisms of AD has been significantly enhanced through the PET amyloid neuroimaging. Currently, amyloid-PET neuroimaging has been a useful tool to estimate b-amyloid plaques during its life. Three radiopharmaceuticals have been approved by the EMA, unfortunately, its use in the nuclear medicine departments in France has remained limited due to the lack of individual community approval.
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