Radiosynthesis and in vivo evaluation of fluorinated huprine
Transcription
Radiosynthesis and in vivo evaluation of fluorinated huprine
Nuclear Medicine and Biology xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect 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