Detection of amyloid in Alzheimer’s disease with positron emission tomography using [11C]AZD2184

European Journal of Nuclear Medicine and Molecular Imaging, Jun 2009

Purpose Current positron emission tomography (PET) radioligands for detection of Aβ amyloid in Alzheimer’s disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [11C]AZD2184 and report here the first clinical evaluation. Methods Eight AD patients and four younger control subjects underwent 93-min PET measurements with [11C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters. Results Brain uptake of [11C]AZD2184 peaked within 1 min at 3–4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57. Conclusion [11C]AZD2184 is a promising radioligand for detailed mapping of Aβ amyloid depositions in Alzheimer’s disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium.

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Detection of amyloid in Alzheimer’s disease with positron emission tomography using [11C]AZD2184

Svante Nyberg Maria Eriksdotter Jnhagen Zsolt Cselnyi Christer Halldin Per Julin Hans Olsson Yvonne Freund-Levi Jan Andersson Katarina Varns Samuel Svensson Lars Farde Purpose Current positron emission tomography (PET) radioligands for detection of A amyloid in Alzheimer's disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [11C]AZD2184 and report here the first clinical evaluation. Methods Eight AD patients and four younger control subjects underwent 93-min PET measurements with [11C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters. Results Brain uptake of [11C]AZD2184 peaked within 1 min at 3-4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57. Conclusion [11C]AZD2184 is a promising radioligand for detailed mapping of A amyloid depositions in Alzheimer's disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium. - Alzheimers disease (AD) is a major cause of dementia estimated to affect more than 30 million people worldwide [1]. While clinical diagnosis is based on symptoms, definite AD diagnosis is based on post-mortem identification of extracellular -amyloid (A) plaques and intraneuronal neurofibrillary tangles. Formation of neuritic plaques by A deposits is thought to play a major role in the pathophysiology of AD, and several therapeutic agents intended to remove or prevent the build-up of amyloid deposits are currently in clinical development. Recent development of positron emission tomography (PET) radioligands for detection of amyloid in patients has provided a new potential for diagnosis of AD during lifetime, ideally before the onset of clinical symptoms. It is also of interest to explore rate and distribution pattern of amyloid formation in relation to clinical progression. However, the first generation of radioligands for PET, including the Pittsburgh compound B ([11C]PIB) [2], are not ideal for quantification due to low signal to noise ratio, high non-specific binding or unfavourable kinetics [3]. We have recently developed the new putative radioligand, 5-(6-{[tert-butyl(dimethyl)silyl]oxy}-1,3-benzothiazol-2-yl) pyridin-2-amine (AZD2184), which has high affinity in vitro for amyloid fibrils [dissociation constant (Kd) 8.41.0 nM] [4]. Autoradiography on cortical brain sections from APP/ PS1 mice and AD patients has shown that [3H]AZD2184 has approximately 3 times higher signal to noise ratio than [3H] PIB, particularly because of lower non-specific binding [4]. Preclinical characterization thus suggests that 11C-labelled AZD2184 may provide higher sensitivity for A amyloid than the reference radioligand [11C]PIB. The aim of this first PET study with [11C]AZD2184 in AD patients and control subjects was to evaluate the suitability of this radioligand for detection and quantification of brain A amyloid. This report is a descriptive summary of the findings. Materials and methods The study was conducted at the PET Centre at Karolinska University Hospital Solna, with AD subjects recruited from the Karolinska University Hospital Memory Clinic at Huddinge, Sweden. The study was approved by the Regional Ethics Committee in Stockholm, Sweden and was performed in accordance with the Declaration of Helsinki and International Conference on Harmonization/Good Clinical Practice guidelines. Written informed consent was obtained from all subjects and caregivers before enrolment. Eight patients fulfilling DSM-IV AD criteria (four female, mean age: 62.6 years, range: 5576) were recruited. AD was characterized according to a routine clinical protocol including the Mini-Mental State Examination (MMSE), brain imaging (MRI or CT), neuropsychological assessments and CSF analyses. Four control subjects (male, mean age: 28.8 years, range: 2336) were recruited. To allow detailed examination of non-specific binding (i.e. the background), young control subjects were chosen to minimize the likelihood of amyloid pathology. Properties and radiosynthesis of [11C]AZD2184 [11C]AZD2184 was produced according to Andersson et al. [5]. [11C]methane was produced in target via the 14N(p,)11C reaction on nitrogen with 10% hydrogen, using 16.4 MeV protons (GEMS PET trace cyclotron). [11C]methane was passed through a heated column containing I2 to produce [11C]methyl iodide via a radical reaction [6]. [11C]methyl iodide was trapped in a vessel containing 2.5 mg of the precursor, 5-(6-(tert-butyldimethyl-silyloxy)benzo[d]thiazol2-yl)pyridin-2-amine), and potassium hydroxide (10 mg) in dimethyl sulphoxide (DMSO) (300 l). Heating at 125C for 5 min was performed followed by deprotection with water (200 l) at room temperature fo (...truncated)


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Svante Nyberg, Maria Eriksdotter Jönhagen, Zsolt Cselényi, Christer Halldin, Per Julin, Hans Olsson, Yvonne Freund-Levi, Jan Andersson, Katarina Varnäs, Samuel Svensson, Lars Farde. Detection of amyloid in Alzheimer’s disease with positron emission tomography using [11C]AZD2184, European Journal of Nuclear Medicine and Molecular Imaging, 2009, pp. 1859, Volume 36, Issue 11, DOI: 10.1007/s00259-009-1182-1