[11C]Befloxatone in the Human Brain, a Selective Radioligand to Image Monoamine Oxidase A

Kinetic analysis of [11C]befloxatone in the human brain, a selective radioligand to image monoamine oxidase A. Paolo Zanotti-Fregonara, Claire Leroy, Dimitri Roumenov, Christian Trichard, Jean-Luc Martinot, Michel Bottlaender To cite this version: Paolo Zanotti-Fregonara, Claire Leroy, Dimitri Roumenov, Christian Trichard, Jean-Luc Martinot, et al.. Kinetic analysis of [11C]befloxatone in the human brain, a selective radioligand toimage monoamine oxidase A.. EJNMMI Research, SpringerOpen, 2013, 3 (1), pp.78. 10.1186/2191-219X- 3-78. inserm-00911737 HAL Id: inserm-00911737 https://www.hal.inserm.fr/inserm-00911737 Submitted on 29 Nov 2013 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Zanotti-Fregonara et al. EJNMMI Research 2013, 3:78 http://www.ejnmmires.com/content/3/1/78 ORIGINALRESEARCH Open Access Kinetic analysis of [11C]befloxatone in the human brain, a selective radioligand to image monoamine oxidase A Paolo Zanotti-Fregonara1*, Claire Leroy2,3, Dimitri Roumenov2, Christian Trichard3, Jean-Luc Martinot3 and Michel Bottlaender2,4 Abstract Background: [11C]Befloxatone measures the density of the enzyme monoamine oxidase A (MAO-A) in the brain. MAO-A is responsible for the degradation of different neurotransmitters and is implicated in several neurologic and 11 psychiatric illnesses. This study sought to estimate the distribution volume (VT) values of [ C]befloxatone in humans using an arterial input function. Methods: Seven healthy volunteers were imaged with positron emission tomography (PET) after [11C]befloxatone injection. Kinetic analysis was performed using an arterial input function in association with compartmental modeling and with the Logan plot, multilinear analysis (MA1), and standard spectral analysis (SA) at both the regional and voxel level. Arterialized venous samples were drawn as an alternative and less invasive input function. Results: An unconstrained two-compartment model reliably quantified VT values in large brain regions. A constrained model did not significantly improve VT identifiability. Similar VT results were obtained using SA; however, the Logan plot and MA1 slightly underestimated VT values (about −10%). At the voxel level, SA showed a very small bias (+2%) compared to compartmental modeling, Logan severely underestimated VT values, and voxel-wise images obtained with MA1 were too noisy to be reliably quantified. Arterialized venous blood samples did not provide a satisfactory alternative input function as the Logan-VT regional values were not comparable to those obtained with arterial sampling in all subjects. Conclusions: Binding of [11C]befloxatone to MAO-A can be quantified using an arterial input function and a two-compartment model or, in parametric images, with SA. Keywords: [11C]Befloxatone; Monoamine oxidase A; PET; Spectral analysis Background thalamus and the occipital cortex, intermediate values are Monoamineoxidase(MAO)isamitochondrialenzymere- found in the basal ganglia, and lower concentrations are sponsible for the degradation of several neurotransmitters, seen in the frontal cortex and cerebellum [1,2]. MAO-A such as dopamine, serotonin, and noradrenaline. Two dysfunction has been implicated in several neurologic ill- MAO isoforms - products of different genes - have been nesses such as Parkinson's disease, Alzheimer's disease, identified in mammals: enzyme monoamine oxidase A and Huntington's disease, as well as in psychiatric diseases (MAO-A), which is primarily found in cathecolaminergic such as major depressive disorder [3]. Notably, several neurons, and MAO-B, which is mainly present in glial cells studies have linked MAO-A enzyme activity and gene and serotonergic neurons [1]. MAO-A is widespread in the expression to tobacco addiction [2,4-7]. human brain; the highest concentrations are found in the With some exceptions [6], studies on MAO-A activity have been hindered by the lack of suitable ligands for this enzyme. For instance, the metabolism rate of [11C] * Correspondence: [email protected] harmine in the plasma is very high, thus making a reli- 1University of Bordeaux, CNRS, INCIA, UMR 5287, Talence 33400, France able quantification of the input function challenging [8], Full list of author information is available at the end of the article © 2013 Zanotti-Fregonara et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zanotti-Fregonara et al. EJNMMI Research 2013, 3:78 Page 2 of 9 http://www.ejnmmires.com/content/3/1/78 and [11C]brofaromine has very little displaceable bind- Each subject also underwent brain T1-weighed three- ing [9]. dimensional magnetic resonance imaging (MRI) using a Befloxatone is a potent, selective, and reversible inhibi- 1.5 T Signa scanner (GE Healthcare, Milwaukee, WI, tor of brain MAO-A activity [10]. It can be radiolabeled USA). MRI images were acquired with a voxel size of with 11C using [11C]phosgene as the reagent [11]. [11C] 0.938 × 0.938 × 1.3 mm3 and a thickness of 1.3 mm in Befloxatone has a highly specific binding to MAO-A, as axial slices. shown by extensive in vitro [10] and in vivo studies in primates [12]. In particular, nonsaturable uptake, ob- Measurement of [11C]befloxatone in arterial and venous tained after a pretreatment with a high dose of unlabeled plasma befloxatone, is very low and represents only 3% of the Arterial blood samples were drawn from the radial artery total uptake [12]. [11C]Befloxatone has good imaging of each subject in 10-s intervals until 2 min, followed by characteristics and has been used in positron emission samples at 3, 4, and 5 min and then every 5 min until tomography (PET) studies to quantify in vivo MAO-A in the end of the scan at 60 min. About 27 samples were rats [13], nonhuman primates [12,14], and humans. In drawn for each subject. For each blood sample, the humans, it has been used to compare MAO-A binding decay-corrected concentration of [11C]befloxatone was potential in smokers and nonsmokers [7]; however, a measured in whole blood and plasma. Plasma was rigorous kinetic modeling study in humans has never obtained by centrifugation. Plasma-free fraction was not been performed. This paper sought to (1) quantify the measured. Venous blood samples were simultaneously uptake of [11C]befloxatone in the human brain, both at drawn from the cubital vein of the opposite arm, using the regional and voxel level, using an arterial input the same number of samples and time schedule as the function; and (2) explore the possibility of replacing the arterial ones. As for arterial blood, plasma was separated arterial input function with a less invasive approach from total venous blood. Arterialization of venous blood based on sampling of arterialized venous blood. was achieved by heating the arm with hot water bags, starting 30 min before ligand injection until the end of Methods the scan. The bags were replaced every 20 to 30 min. Subjects Four or five times during each scan, blood gases Seven healthy, nonsmoker, male volunteers (72 ± 9.5 kg, (pO2 and pCO2) were measured in five subjects. age 26 ± 4.5 years) from a previous clinical protocol were The whole plasma time-activity curves were taken as included in this study [7]. All subjects were free of current input functions because in a previous series of (yet medical or psychiatric illnesses and had no history of unpublished) four human scans from our laboratory, drug or alcohol abuse. Subjects were instructed to avoid chromatograms obtained with high-performance liquid monoamine-rich food 3 days before and alcohol consump- chromatography (HPLC) did not show any detectable tion 1 week before imaging. Vital signs (blood pressure, radiometabolites in the plasma, even at late time points. heart rate) were recorded before [11C]befloxatone injec- The technique we used to measure the amount of tion and at the end of the scan. The study was approved unchanged radiotracer in the plasma was similar to that by the regional ethics committee for biomedical research described in [14]. Specifically, after deproteinization with at the Bicêtre Hospital. Each subject gave a written infor- acetonitrile, the samples were centrifuged and the super- med consent. natant was injected directly into the HPLC column. A reverse-phase μBondapak C18 column (300 × 7.8 mm, Brain image acquisition 10 μm; Waters, Milford, MA, USA) was eluted applying PET scans were performed on an ECAT EXACT HR + a gradient from 20% acetonitrile in 0.01 M phosphoric scanner (Siemens Medical Solutions, Knoxville, TN, USA). acid up to 80% in 5.5 min, to 90% at 7.5 min, and One transmission scan was acquired before intravenous returning to 20% at 7.6 min with a total run length of bolus injection of [11C]befloxatone (290 ± 24.4 MBq). The 10 min. The flow rate of the eluent was maintained at specific activity was 35.2 ± 14.9 GBq/μmol, which is within 6 mL/min. Befloxatone was eluted with a retention time the range of the values usually obtained from the synthesis of 6 min. Data acquisition and analysis were carried out of [11C]befloxatone [11] and sufficient to rule out any using Winflow software (version 1.21, JMBS Developments, mass effect. Even when considering a conservative Bmax Grenoble, France). value of 99 pmol/mL (as found in vitro in the human cerebellum [14]), the Bmax occupancy is well below 1% in Brain image analysis each subject.

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