Radiosynthesis and in vivo evaluation of fluorinated huprine

Nuclear Medicine and Biology xxx (2013) xxx–xxx
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Nuclear Medicine and Biology
journal homepage: www.elsevier.com/locate/nucmedbio
Radiosynthesis and in vivo evaluation of fluorinated huprine derivates as PET
radiotracers of acetylcholinesterase
Emilie Da Costa Branquinho a, b, Guillaume Becker c, d, Cédric Bouteiller a, Ludovic Jean b,
Pierre-Yves Renard b, Luc Zimmer c, d,⁎
a
Advanced Accelerator Applications, Saint-Genis-Pouilly, France
Normandie Université; Univ. Rouen, FR 3038; INSA Rouen; CNRS, UMR 6014 ; COBRA, Mont Saint-Aignan, France
c
University of Lyon; Univ. Claude Bernard Lyon1 ; CNRS, UMR 5292 ; INSERM, U1028; Lyon Neuroscience Research Center, Lyon, France
d
Hospices Civils de Lyon, CERMEP-Imaging Platform, Lyon, France
b
a r t i c l e
i n f o
Article history:
Received 2 January 2013
Received in revised form 4 February 2013
Accepted 4 February 2013
Available online xxxx
Keywords:
Acetylcholinesterase
PET
Huprine
Rat
Cat
P-glycoprotein
a b s t r a c t
Introduction: Developing positron emission tomography (PET) radiotracers for non-invasive study of the
cholinergic system is crucial to the understanding of neurodegenerative diseases. Although several
acetylcholinesterase (AChE) PET tracers radiolabeled with carbon-11 exist, no fluorinated radiotracer is
currently used in clinical imaging studies. The purpose of the present study is to describe the first fluorinated
PET radiotracer for this brain enzyme.
Methods: Three structural analogs of huprine, a specific AChE inhibitor presenting high affinity towards AChE
in vitro, were synthesized and labeled with fluorine-18 via a mesylate/fluoro-nucleophilic aliphatic
substitution: ([ 18 F]-FHUa, [ 18 F]-FHUb and [18 F]-FHUc). Initial biological evaluation included in vitro
autoradiography in rat with competition with an AChE inhibitor at different concentrations, and microPETscan on anesthetized rats. In vivo PET studies in anesthetized cat focused on [18 F]-FHUa.
Results and Conclusions: Although radiosynthesis of these huprine analogs was straightforward, they showed
poor brain penetration potential, partially reversed after pharmacological inhibition of P-glycoprotein. These
results indicated that current huprine analogs are not suitable for PET mapping of brain AChE receptors, but
require physicochemical modulation in order to increase brain penetration.
© 2013 Elsevier Inc. All rights reserved.
1. Introduction
Acetylcholinesterase (AChE) is the enzyme that catalyzes the
degradation of the neurotransmitter acetylcholine, terminating
cholinergic neurotransmission. Both clinical and postmortem studies
indicate that, as the cholinergic axons degenerate, AChE activity is
reduced, leading to biochemical changes in the brain of Alzheimer’s
disease (AD) patients. Therefore, degeneration of the cholinergic
neurons of the basal forebrain and their projections is widely seen as
an early pivotal event in AD [1]; there is also evidence for interaction
with amyloid deposition and plaque formation [2,3].
In vivo PET imaging of AChE with specifically prepared radioligands can be used to map these cholinergic enzymes in the brain of
animal models or patients, and can potentially assess the involvement
of the cholinergic system in neurodegenerative diseases (e.g., AD or
Lewy body disease), enabling diagnosis and assessment of current and
future therapies. Because AChE is not strictly limited to presynaptic
⁎ Corresponding author.
E-mail address: [email protected] (L. Zimmer).
sites [4], PET imaging can measure the pre- and post-synaptic
integrity of cholinergic transmission in general.
PET AChE radiotracers are available [5], using two different
radiopharmacological approaches [6]. The first method uses a
radiolabeled lipophilic acetylcholine analog that enters the brain,
where it is metabolized by AChE to produce a hydrophilic metabolite
that becomes trapped. Different radiolabeled analogs of acetylcholine,
substrates for AChE, are used for measuring and imaging its activity in
vivo: i.e., N- 11C-methylpiperidine-4-yl propionate ([ 11C]-PMP),
and N- 11C-methylpiperidyl-4-yl acetate ([ 11C]-MP4A or [ 11C]-AMP).
Both have been used to measure AChE activity [7–10] and a
modification of their binding was found in AD patients, compared
with healthy controls [11]. The second method uses radiolabeled
AChE inhibitors: i.e., [ 11C]-physostigmine [12] or [ 11C]-donepezil [13].
If these inhibitors reach the brain, they show longer retention in
cerebral areas that are rich in AChE, such as the striatum, compared to
the cerebral cortex.
Given these successes in using [ 11C]-labeled PET radiotracers,
research quickly focused on series of [ 18 F]-labeled analogs [14].
Fluorinated compounds would be more convenient for PET imaging,
allowing longer acquisition times, which are useful if radiotracers
0969-8051/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.nucmedbio.2013.02.004
Please cite this article as: Da Costa Branquinho E, et al, Radiosynthesis and in vivo evaluation of fluorinated huprine derivates as PET
radiotracers of acetylcholinesterase, Nucl Med Biol (2013), http://dx.doi.org/10.1016/j.nucmedbio.2013.02.004