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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.
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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)