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Simplified quantification of nicotinic receptors with 2[18F]F-A-85380 PET
Nuclear Medicine and Biology 32 (2005) 585 – 591 www.elsevier.com/locate/nucmedbio
Simplified quantification of nicotinic receptors with 2[18F]F-A-85380 PET Sascha Mitkovskia, Victor L. Villemagnea,b,c, Kathy E. Novakovica,c, Graeme O’Keefea, Henri Tochon-Danguya, Rachel S. Mulligana, Kerryn L. Dickinsona, Tim Saundera, Marie-Claude Gregoired, Michel Bottlaenderd, Frederic Dolled, Christopher C. Rowea,e,T a
Department of Nuclear Medicine and Centre for PET, Austin Hospital, 145 Studley Road, Victoria 3084, Melbourne, Australia b Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia c Department of Pathology, University of Melbourne, Victoria 3010, Australia d CEA Service Hospitalier Frederic Joliot, DRM/DSV, CEA, 91401 Orsay CEDEX, France e Department of Medicine, University of Melbourne, Victoria 3010, Australia Received 4 April 2005; received in revised form 26 April 2005; accepted 26 April 2005
Abstract Introduction: Neuronal nicotinic acetylcholine receptors (nAChRs), widely distributed in the human brain, are implicated in various neurophysiological processes as well as being particularly affected in neurodegenerative conditions such as Alzheimer’s disease. We sought to evaluate a minimally invasive method for quantification of nAChR distribution in the normal human brain, suitable for routine clinical application, using 2[18F]F-A-85380 and positron emission tomography (PET). Methods: Ten normal volunteers (four females and six males, aged 63.40F9.22 years) underwent a dynamic 120-min PET scan after injection of 226 MBq 2[18F]F-A-85380 along with arterial blood sampling. Regional binding was assessed through standardized uptake value (SUV) and distribution volumes (DV) obtained using both compartmental (DV2CM) and graphical analysis (DVLogan). A simplified approach to the estimation of DV (DVsimplified), defined as the region-to-plasma ratio at apparent steady state (90–120 min post injection), was compared with the other quantification approaches. Results: DVLogan values were higher than DV2CM. A strong correlation was observed between DVsimplified, DVLogan (r = .94) and DV2CM (r = .90) in cortical regions, with lower correlations in thalamus (r = .71 and .82, respectively). Standardized uptake value showed low correlation against DVLogan and DV2CM. Conclusion: DVsimplified determined by the ratio of tissue to metabolite-corrected plasma using a single 90- to 120-min PET acquisition appears acceptable for quantification of cortical nAChR binding with 2[18F]F-A-85380 and suitable for clinical application. D 2005 Elsevier Inc. All rights reserved. Keywords: Nicotinic acetylcholine receptors; 2[18F]F-A-85380; Alzheimer’s disease; Positron emission tomography; Neurodegenerative disorders; Brain imaging
1. Introduction Neuronal nicotinic acetylcholine receptors (nAChRs) in mammals are found in the central and peripheral nervous system, neuromuscular junctions and adrenal glands. Cerebral nAChRs belong to the superfamily of ligandgated cation channels and are composed of protein subunits (a and h) associated in homologous or heterologous pentameric channels, permeable to sodium (Na+),
T Corresponding author. Department of Nuclear Medicine, Centre for PET, Austin Health, Heidelberg, Victoria 3084, Australia. Tel.: +61 3 9496 5183; fax: +61 3 9458 5023. E-mail address: [email protected] (C.C. Rowe). 0969-8051/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.nucmedbio.2005.04.013
potassium (K+) and calcium (Ca2+) [1]. The majority of cerebral nAChRs are of the a4h2 subtype [1,2], characterized by their high affinity for () nicotine, labeled by agonists such as 3H-acetylcholine, 3H-nicotine, 3H-cytisine and 3 H-epibatidine [3], and low affinity for 125I-a-bungarotoxin [4] that binds with high affinity to a7 nAChR subtype [5]. Located on pre-, post- and extrasynaptic sites where they exert their modulatory actions, nAChRs are involved in a series of crucial physiological higher cognitive functions such as learning and memory, cognition and arousal [5,6]. Cerebral nAChRs play multiple roles in signal transduction including fast synaptic transmission [7], auto-axonic transmission [8] and modulation of presynaptic transmitter release, including the secretion of both excitatory and
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inhibitory transmitters such as acetylcholine, dopamine, gamma-amino butyric acid, glutamate, norepinephrine and serotonin [9,10]. Postmortem studies have demonstrated a decline in nAChRs with aging in the human brain [3,5,6], particularly frontal and temporal cortices for both [3H]-epibatidine (79% and 84%, respectively) and [3H]-nicotine binding (82% and 79% respectively) between the ages of 56 and 85 years [3], with some data suggesting a sparing of the thalamus [11,12]. Cerebral nAChRs have been implicated in the pathophysiology and/or treatment strategies of Alzheimer’s [13–16] and Parkinson’s diseases [17], epilepsy [18], schizophrenia [19], Tourette’s syndrome [20], anxiety [21], depression [22] and nicotine dependence [23]. There is a selective loss of both high-affinity nicotinic binding sites and the a4 subunit from the cerebral cortex in AD, correlating with the severity of dementia [5,6]. Studies have revealed deficits of nAChRs (between 25% and 75%) in temporal and frontal cortices and hippocampal regions of AD patients by in vitro binding assays [6]. In vivo assessment of nAChR in AD patients with [11C]-nicotine and PET showed a reduction in binding sites [2,24]; however, [11C]-nicotine characteristics as a ligand for quantification of nAChRs in vivo via PET are less than ideal. This is mainly due to the fact that its uptake is mediated principally by regional cerebral blood flow [25]. The discovery of epibatidine, a potent nAChR agonist [26], stimulated development of nAChR radioligands with more favorable properties for PET studies. These ligands displayed superb binding properties toward the a4h2 subtype [27], but had a narrow safety margin that severely limited their use in humans [28]. The recently developed azetidine derivative of the 3-pyridyl ethers A85380 (3-[2(S)-2-azetidinylmethoxyl]pyridine), a weak agonist with high affinity for the a4h2 subtype nAChR [29], showed suitable properties for imaging nAChRs in vivo with both PET and single-photon emission tomography (SPECT) [30,31]. Radiolabelling of A85380 with 18F (t 1/2 =109 min) was achieved without alteration of its receptor binding characteristics [31,32]. The first human PET studies with 2[18F]F-A-85380 showed that maximal radioactivity uptake (2.5% ID) in the human brain was reached between 50 and 80 min postinjection [33,34]. Tissue-to-plasma ratios for 2[18F]F-A-85380 stabilised very slowly for most regions except the thalamus, where no equilibrium was reached over a 4-h scanning period [35]. Positron emission tomography and SPECT studies in both primates and humans validated the use of compartmental and graphical approaches for the quantification of nAChRs with 2[18F]F-A-85380 or its analogs [36]. In this study, we aimed to develop a simplified method for quantifying nAChRs in humans using 2[18F]F-A-85380 and PET suitable for research and clinical applications, particularly in elderly or cognitively impaired subjects who may not be able to tolerate either a prolonged scan and/or arterial blood sampling.
2. Methods 2.1. Demographics Ten normal volunteers (four females, six males) aged 63.40F9.22 years (range 49 –76) were recruited from the community by advertisement. Written informed consent for participation in this study was obtained prior to the scan. Approval was obtained for the study from the Austin Health Human Research Ethics Committee, Austin Radiation Subcommittee and the Victorian Department of Human Services Radiation Safety Unit. Subjects had no history of progressive cognitive decline, a Mini-Mental State Examination score of 27 or above and a Clinical Dementia Rating score of 0. The exclusion criteria included cerebrovascular disease evidenced as focal neurological signs or stroke-related changes on MRI, evidence of any brain disorder or mental illness, smoking, contraindication to a MRI scan and use of medications with cholinergic or anticholinergic action. 2.2. Magnetic resonance imaging All subjects underwent a 3D spoiled gradient echo T1-weighed acquisition on a GE Sigma 1.5-T MRI scanner, for screening and subsequent coregistration with the PET images. 2.3. Radiolabelling Production of 2[18F]F-A-85380 was performed in the Department of Nuclear Medicine and Center for PET, Austin Hospital, according to the method of Dolle´ et al. [31]. A-85380 was labelled with 18F to position 2 of the pyridine ring by no-carrier-added nucleophilic aromatic trimethylammonium-to-fluoro substitution by K-[18F]F-K222 complex with 3-[2(S)-N-(tert-butoxycarbonyl) 2-azetidinylmethoxy] pyridine)-2-yl trimethylammonium trifluoromethanesulfonate, followed by trifluoroacetic acid removal of the Boc protective group. The total synthesis time was 50 min from the end of bombardment including HPLC purification. The radiochemical purity was above 99%. The specific radioactivity of the final product was N 37 GBq/Amol at the time of injection. Each subject received 226F36.57 MBq (range 180–270) of 2[18F]F-A-85380 by injection into the right antecubital vein over 1 min. 2.4. Positron emission tomography Dynamic imaging was performed with an ECAT 951/31R PET camera (Siemens/CTI). An 8-min transmission scan was performed before the injection of the radioligand using a 68 Ge rod source in the 2D mode. A 2-h dynamic emission brain scan was performed in 3D mode (septa retracted) after intravenous injection of 2[18F]F-A-85380 over 1 min. The PET acquisition protocol consisted of 630-s, 61-min, 63-min, 66-min and 610-min frames, respectively. Images were reconstructed using a 3D-reconstruction algorithm, based on the filtering back projection method of
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Fig. 1. Percentage of injected dose per 100 ml (%ID/100 ml) as a function of time for thalamus, cerebellum, frontal cortex and white matter (ID 226F36.57 MBq).
Kinahan and Rogers [37]. The PET scanner calibration factor was determined using a 68Ge phantom in 3D mode. Coregistration of the PET images with the MRI was performed with SPM-99 (Statistical Parametric Mapping, MRC Cognition and Brain Sciences Unit) [38]. 2.5. Arterial blood sampling An arterial line was inserted into the left radial artery for automatic blood sampling. Blood radioactivity was assessed using the ECAT scanner automatic blood counter with on-
line radiation detectors. The initial continual sampling lasted for 20 min, followed by periodic sampling at 30, 45, 60, 90 and 120 min. Discrete blood and plasma samples were measured in a Wallac Wizard gamma counter. Plasma radioactivity measurements were metabolite and decay corrected [35]. 2.6. Data analysis The mean of the top 30% of pixel counts was determined in MRI-defined ROI for frontal cortex, thalamus, cerebellum
Fig. 2. Uncorrected vs. metabolite corrected plasma in one subject (ID 206 MBq). Correction for metabolites was performed using an equation developed at the DRM/DSV, CEA (Orsay, France): Unchanged fraction = 0.3786{exp[ln (2)(sampling time)/15.2+(10.3786)]}, where 15.2 min reflects the time delay in which no 2[18F]F-A-85380 metabolites were detected.
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and white matter, and converted to kilobecquerel per millilitre. Decay-corrected time–activity curves (TAC) were generated for cortical, subcortical and cerebellar regions. Standardized uptake values (SUV) for thalamus, frontal cortex and cerebellum were determined at 90 to 120 min using the injected dose (ID) and body weight. Time–activity curves were examined to determine a suitable quantification approach for receptor binding. Due to the widespread distribution of nAChR, there is no region devoid of receptors suitable for use to establish nonspecific binding. Therefore, due to its apparent reversible binding and the different quantification approaches used for 2[18F]F-A-85380 and its analogues [36], both two-compartment model (one-tissue compartment) [35] and graphical [39,40] analyses were applied, using metabolite-corrected arterial plasma and brain regional uptake, for determination of distribution volume (DV). Distribution volume in the two-compartment approach (DV2CM) is equivalent to K 1/k 2. In the graphical analysis approach, DV (DVLogan) is the slope of the linear section of the plot of: ZT 0
CTissue ðt Þdt=CTissue ðT Þ vs:
ZT
CP ðt Þdt=CTissue ðT Þ
0
where C Tissue is the decay-corrected PET radioactivity concentration in brain regions, and C P is the metaboliteand decay-corrected plasma radioactivity [39]. A simplified DV (DVsimplified) was defined as the brain-to-arterial plasma ratio at 90–120 min postinjection. To further simplify the method, a comparison of arterial vs. venous plasma activity was performed at 2 h postinjection in three subsequent subjects, to assess the suitability of venous instead of arterial plasma samples in the DVsimplified approach.
Table 1 Quantification approaches used to estimate nAChR DV Region Cerebellum Frontal Ctx Thalamus
Quantification method DVsimplified
DVLogan
DV2CM
5.82F1.67 5.53F1.66 8.35F1.84
6.14F1.37 5.59F1.37 10.29F2.09
5.28F1.01 4.70F0.95 8.01F2.35
Values represent meanFS.D.
Pearson correlation coefficients were used for the comparison of the SUV and DVsimplified with the results of DV2CM and DVLogan. 3. Results 3.1. Regional brain kinetics The brain uptake of 2[18F]F-A-85380 was consistent with the known distribution of nAChRs [12]. Higher uptake and slower clearance of the radioligand in the thalamus compared with the other regions were clearly evident. In most subjects, 2[18F]F-A-85380 uptake in the thalamus approached a plateau around 90 min postinjection (93F15.8 min). Cortical regions reached maximal uptake approximately at 60 min postinjection (61F9.4 min), followed by a slow washout, while the cerebellum peaked at around 50 min postinjection (52F9.5 min), followed by a slightly faster clearance than cortical regions. Though presenting the lowest uptake, white matter radioactivity increased slowly throughout the 2-h scan (Fig. 1). 3.2. Plasma kinetics of 2[18F]F-A-85380 A rapid peak of 2.06F0.7 % of ID/100 ml of decaycorrected plasma was followed first by a fast and then a slower exponential clearance (Fig. 2). There was little
Fig. 3. MeanFS.E.M. tissue-to-blood ratios as a function of time for thalamus, cerebellum and frontal cortex (ID 226F36.57 MBq).
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difference observed between venous and arterial plasma radioactivity at 120 min postinjection, with venous plasma 4.2%F0.04 higher than arterial plasma. At 120 min postinjection, 62% of the plasma radioactivity corresponded to unmetabolized 2[18F]F-A-85380 (Fig. 2). Fig. 3 shows the mean ratio of regional brain to metabolite-corrected plasma activity for the thalamus, cerebellum and frontal cortex over the 120-min study period, suggesting that steady state is achieved for cortical
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regions after 90 min postinjection, but not for the thalamus that shows an increasing ratio over the 120-min study. 3.3. Quantification of nAChRs DV values for selected brain regions are shown in Table 1. Comparison of DVsimplified against DVLogan and DV2CM yielded a very high correlation for both frontal cortex (r =.94 and .90 for DVLogan and DV2CM, respectively) and cerebellum (r = .92 and .88 for DVLogan and DV2CM, respectively),
Fig. 4. Analysis of correlation between DVLogan, DV2CM and DVsimplified values derived from 120-min PET scans, in cerebellum, frontal cortex and thalamus. Extrathalamic regions demonstrated high correlation indices. Lower correlations were observed in the thalamus.
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Table 2 Correlation (and P) values for different quantification approaches DVsimplified
SUV
Cerebellum Frontal Ctx Thalamus Cerebellum Frontal Ctx Thalamus
DVLogan
DV2CM
0.92 0.94 0.71 0.18 0.25 0.20
0.88 0.90 0.82 0.44 0.52 0.27
( P b.001) ( P b.001) ( P = .02) ( P = .62) ( P = .48) ( P = .58)
( P b.001) ( P b.001) ( P = .003) ( P = .21) ( P = .12) ( P = .44)
with lower correlation for thalamus (r =.71 and .82 for DVLogan and DV2CM, respectively) (Fig. 4). The correlation between SUVs and the DVLogan and DV2CM was lower and not statistically significant (Table 2). 4. Discussion and conclusion The binding of 2[18F]F-A-85380 as visualized by PET showed the highest uptake in the thalamus, modest uptake in the cerebellum and cortex, and lowest in white matter. Though consistent with the known distribution of nAChR as determined by in vitro and in vivo studies, the uptake in the cerebellum and white matter was greater than expected from previous in vitro human and animal studies of nAChR binding with agents such as [3H]-nicotine and [3H]-epibatidine [41]. While nAChRs are not found in the cerebellum of rodents [42] or Rhesus monkeys [40], significant numbers are present in baboons [27,43] and humans [34,35], suggesting marked species differences in nAChR regional distribution. Time–activity curves for white matter showed progressive accumulation despite a rapid decline in blood levels of 2[18F]F-A-85380, which suggests some specific binding. White matter binding has been previously reported with PET [44,45], and autoradiography using 125I-labelled A-85380 has shown binding in specific white matter tracts [46]. Though the binding to white matter has been attributed to either intraxonal presynaptic receptors undergoing axonal transport [46], axonal postsynaptic receptors of axo-axonal synapses or astrogial receptors [47,48], a full explanation for this apparent specific binding has not been elucidated. Previous reports have shown that 2[18F]F-A-85380 has acceptable radiation dosimetry and no toxic effects at the tracer doses used in PET [33], supporting its potential use in clinical studies. However, the continuous dynamic PET acquisition for 2 h with frequent arterial blood sampling and metabolite correction employed in this study is arduous, time consuming and a hindrance to clinical studies, particularly when the subjects of most interest are either elderly and/or cognitively impaired. A minimum scan duration of 120 min is required for graphical or compartmental analysis of cortical nAChR by 2[18F]F-A-85380, as recently demonstrated [35]. Consequently, we implemented and evaluated simplified methods of quantification, SUV and DVsimplified, against graphical analysis and compartmental modeling. Standardized uptake value is a commonly
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Simplified quantification of nicotinic receptors with 2[18F]F-A-85380 PET Sascha Mitkovskia, Victor L. Villemagnea,b,c, Kathy E. Novakovica,c, Graeme O’Keefea, Henri Tochon-Danguya, Rachel S. Mulligana, Kerryn L. Dickinsona, Tim Saundera, Marie-Claude Gregoired, Michel Bottlaenderd, Frederic Dolled, Christopher C. Rowea,e,T a
Department of Nuclear Medicine and Centre for PET, Austin Hospital, 145 Studley Road, Victoria 3084, Melbourne, Australia b Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia c Department of Pathology, University of Melbourne, Victoria 3010, Australia d CEA Service Hospitalier Frederic Joliot, DRM/DSV, CEA, 91401 Orsay CEDEX, France e Department of Medicine, University of Melbourne, Victoria 3010, Australia Received 4 April 2005; received in revised form 26 April 2005; accepted 26 April 2005
Abstract Introduction: Neuronal nicotinic acetylcholine receptors (nAChRs), widely distributed in the human brain, are implicated in various neurophysiological processes as well as being particularly affected in neurodegenerative conditions such as Alzheimer’s disease. We sought to evaluate a minimally invasive method for quantification of nAChR distribution in the normal human brain, suitable for routine clinical application, using 2[18F]F-A-85380 and positron emission tomography (PET). Methods: Ten normal volunteers (four females and six males, aged 63.40F9.22 years) underwent a dynamic 120-min PET scan after injection of 226 MBq 2[18F]F-A-85380 along with arterial blood sampling. Regional binding was assessed through standardized uptake value (SUV) and distribution volumes (DV) obtained using both compartmental (DV2CM) and graphical analysis (DVLogan). A simplified approach to the estimation of DV (DVsimplified), defined as the region-to-plasma ratio at apparent steady state (90–120 min post injection), was compared with the other quantification approaches. Results: DVLogan values were higher than DV2CM. A strong correlation was observed between DVsimplified, DVLogan (r = .94) and DV2CM (r = .90) in cortical regions, with lower correlations in thalamus (r = .71 and .82, respectively). Standardized uptake value showed low correlation against DVLogan and DV2CM. Conclusion: DVsimplified determined by the ratio of tissue to metabolite-corrected plasma using a single 90- to 120-min PET acquisition appears acceptable for quantification of cortical nAChR binding with 2[18F]F-A-85380 and suitable for clinical application. D 2005 Elsevier Inc. All rights reserved. Keywords: Nicotinic acetylcholine receptors; 2[18F]F-A-85380; Alzheimer’s disease; Positron emission tomography; Neurodegenerative disorders; Brain imaging
1. Introduction Neuronal nicotinic acetylcholine receptors (nAChRs) in mammals are found in the central and peripheral nervous system, neuromuscular junctions and adrenal glands. Cerebral nAChRs belong to the superfamily of ligandgated cation channels and are composed of protein subunits (a and h) associated in homologous or heterologous pentameric channels, permeable to sodium (Na+),
T Corresponding author. Department of Nuclear Medicine, Centre for PET, Austin Health, Heidelberg, Victoria 3084, Australia. Tel.: +61 3 9496 5183; fax: +61 3 9458 5023. E-mail address: [email protected] (C.C. Rowe). 0969-8051/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.nucmedbio.2005.04.013
potassium (K+) and calcium (Ca2+) [1]. The majority of cerebral nAChRs are of the a4h2 subtype [1,2], characterized by their high affinity for () nicotine, labeled by agonists such as 3H-acetylcholine, 3H-nicotine, 3H-cytisine and 3 H-epibatidine [3], and low affinity for 125I-a-bungarotoxin [4] that binds with high affinity to a7 nAChR subtype [5]. Located on pre-, post- and extrasynaptic sites where they exert their modulatory actions, nAChRs are involved in a series of crucial physiological higher cognitive functions such as learning and memory, cognition and arousal [5,6]. Cerebral nAChRs play multiple roles in signal transduction including fast synaptic transmission [7], auto-axonic transmission [8] and modulation of presynaptic transmitter release, including the secretion of both excitatory and
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inhibitory transmitters such as acetylcholine, dopamine, gamma-amino butyric acid, glutamate, norepinephrine and serotonin [9,10]. Postmortem studies have demonstrated a decline in nAChRs with aging in the human brain [3,5,6], particularly frontal and temporal cortices for both [3H]-epibatidine (79% and 84%, respectively) and [3H]-nicotine binding (82% and 79% respectively) between the ages of 56 and 85 years [3], with some data suggesting a sparing of the thalamus [11,12]. Cerebral nAChRs have been implicated in the pathophysiology and/or treatment strategies of Alzheimer’s [13–16] and Parkinson’s diseases [17], epilepsy [18], schizophrenia [19], Tourette’s syndrome [20], anxiety [21], depression [22] and nicotine dependence [23]. There is a selective loss of both high-affinity nicotinic binding sites and the a4 subunit from the cerebral cortex in AD, correlating with the severity of dementia [5,6]. Studies have revealed deficits of nAChRs (between 25% and 75%) in temporal and frontal cortices and hippocampal regions of AD patients by in vitro binding assays [6]. In vivo assessment of nAChR in AD patients with [11C]-nicotine and PET showed a reduction in binding sites [2,24]; however, [11C]-nicotine characteristics as a ligand for quantification of nAChRs in vivo via PET are less than ideal. This is mainly due to the fact that its uptake is mediated principally by regional cerebral blood flow [25]. The discovery of epibatidine, a potent nAChR agonist [26], stimulated development of nAChR radioligands with more favorable properties for PET studies. These ligands displayed superb binding properties toward the a4h2 subtype [27], but had a narrow safety margin that severely limited their use in humans [28]. The recently developed azetidine derivative of the 3-pyridyl ethers A85380 (3-[2(S)-2-azetidinylmethoxyl]pyridine), a weak agonist with high affinity for the a4h2 subtype nAChR [29], showed suitable properties for imaging nAChRs in vivo with both PET and single-photon emission tomography (SPECT) [30,31]. Radiolabelling of A85380 with 18F (t 1/2 =109 min) was achieved without alteration of its receptor binding characteristics [31,32]. The first human PET studies with 2[18F]F-A-85380 showed that maximal radioactivity uptake (2.5% ID) in the human brain was reached between 50 and 80 min postinjection [33,34]. Tissue-to-plasma ratios for 2[18F]F-A-85380 stabilised very slowly for most regions except the thalamus, where no equilibrium was reached over a 4-h scanning period [35]. Positron emission tomography and SPECT studies in both primates and humans validated the use of compartmental and graphical approaches for the quantification of nAChRs with 2[18F]F-A-85380 or its analogs [36]. In this study, we aimed to develop a simplified method for quantifying nAChRs in humans using 2[18F]F-A-85380 and PET suitable for research and clinical applications, particularly in elderly or cognitively impaired subjects who may not be able to tolerate either a prolonged scan and/or arterial blood sampling.
2. Methods 2.1. Demographics Ten normal volunteers (four females, six males) aged 63.40F9.22 years (range 49 –76) were recruited from the community by advertisement. Written informed consent for participation in this study was obtained prior to the scan. Approval was obtained for the study from the Austin Health Human Research Ethics Committee, Austin Radiation Subcommittee and the Victorian Department of Human Services Radiation Safety Unit. Subjects had no history of progressive cognitive decline, a Mini-Mental State Examination score of 27 or above and a Clinical Dementia Rating score of 0. The exclusion criteria included cerebrovascular disease evidenced as focal neurological signs or stroke-related changes on MRI, evidence of any brain disorder or mental illness, smoking, contraindication to a MRI scan and use of medications with cholinergic or anticholinergic action. 2.2. Magnetic resonance imaging All subjects underwent a 3D spoiled gradient echo T1-weighed acquisition on a GE Sigma 1.5-T MRI scanner, for screening and subsequent coregistration with the PET images. 2.3. Radiolabelling Production of 2[18F]F-A-85380 was performed in the Department of Nuclear Medicine and Center for PET, Austin Hospital, according to the method of Dolle´ et al. [31]. A-85380 was labelled with 18F to position 2 of the pyridine ring by no-carrier-added nucleophilic aromatic trimethylammonium-to-fluoro substitution by K-[18F]F-K222 complex with 3-[2(S)-N-(tert-butoxycarbonyl) 2-azetidinylmethoxy] pyridine)-2-yl trimethylammonium trifluoromethanesulfonate, followed by trifluoroacetic acid removal of the Boc protective group. The total synthesis time was 50 min from the end of bombardment including HPLC purification. The radiochemical purity was above 99%. The specific radioactivity of the final product was N 37 GBq/Amol at the time of injection. Each subject received 226F36.57 MBq (range 180–270) of 2[18F]F-A-85380 by injection into the right antecubital vein over 1 min. 2.4. Positron emission tomography Dynamic imaging was performed with an ECAT 951/31R PET camera (Siemens/CTI). An 8-min transmission scan was performed before the injection of the radioligand using a 68 Ge rod source in the 2D mode. A 2-h dynamic emission brain scan was performed in 3D mode (septa retracted) after intravenous injection of 2[18F]F-A-85380 over 1 min. The PET acquisition protocol consisted of 630-s, 61-min, 63-min, 66-min and 610-min frames, respectively. Images were reconstructed using a 3D-reconstruction algorithm, based on the filtering back projection method of
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Fig. 1. Percentage of injected dose per 100 ml (%ID/100 ml) as a function of time for thalamus, cerebellum, frontal cortex and white matter (ID 226F36.57 MBq).
Kinahan and Rogers [37]. The PET scanner calibration factor was determined using a 68Ge phantom in 3D mode. Coregistration of the PET images with the MRI was performed with SPM-99 (Statistical Parametric Mapping, MRC Cognition and Brain Sciences Unit) [38]. 2.5. Arterial blood sampling An arterial line was inserted into the left radial artery for automatic blood sampling. Blood radioactivity was assessed using the ECAT scanner automatic blood counter with on-
line radiation detectors. The initial continual sampling lasted for 20 min, followed by periodic sampling at 30, 45, 60, 90 and 120 min. Discrete blood and plasma samples were measured in a Wallac Wizard gamma counter. Plasma radioactivity measurements were metabolite and decay corrected [35]. 2.6. Data analysis The mean of the top 30% of pixel counts was determined in MRI-defined ROI for frontal cortex, thalamus, cerebellum
Fig. 2. Uncorrected vs. metabolite corrected plasma in one subject (ID 206 MBq). Correction for metabolites was performed using an equation developed at the DRM/DSV, CEA (Orsay, France): Unchanged fraction = 0.3786{exp[ln (2)(sampling time)/15.2+(10.3786)]}, where 15.2 min reflects the time delay in which no 2[18F]F-A-85380 metabolites were detected.
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and white matter, and converted to kilobecquerel per millilitre. Decay-corrected time–activity curves (TAC) were generated for cortical, subcortical and cerebellar regions. Standardized uptake values (SUV) for thalamus, frontal cortex and cerebellum were determined at 90 to 120 min using the injected dose (ID) and body weight. Time–activity curves were examined to determine a suitable quantification approach for receptor binding. Due to the widespread distribution of nAChR, there is no region devoid of receptors suitable for use to establish nonspecific binding. Therefore, due to its apparent reversible binding and the different quantification approaches used for 2[18F]F-A-85380 and its analogues [36], both two-compartment model (one-tissue compartment) [35] and graphical [39,40] analyses were applied, using metabolite-corrected arterial plasma and brain regional uptake, for determination of distribution volume (DV). Distribution volume in the two-compartment approach (DV2CM) is equivalent to K 1/k 2. In the graphical analysis approach, DV (DVLogan) is the slope of the linear section of the plot of: ZT 0
CTissue ðt Þdt=CTissue ðT Þ vs:
ZT
CP ðt Þdt=CTissue ðT Þ
0
where C Tissue is the decay-corrected PET radioactivity concentration in brain regions, and C P is the metaboliteand decay-corrected plasma radioactivity [39]. A simplified DV (DVsimplified) was defined as the brain-to-arterial plasma ratio at 90–120 min postinjection. To further simplify the method, a comparison of arterial vs. venous plasma activity was performed at 2 h postinjection in three subsequent subjects, to assess the suitability of venous instead of arterial plasma samples in the DVsimplified approach.
Table 1 Quantification approaches used to estimate nAChR DV Region Cerebellum Frontal Ctx Thalamus
Quantification method DVsimplified
DVLogan
DV2CM
5.82F1.67 5.53F1.66 8.35F1.84
6.14F1.37 5.59F1.37 10.29F2.09
5.28F1.01 4.70F0.95 8.01F2.35
Values represent meanFS.D.
Pearson correlation coefficients were used for the comparison of the SUV and DVsimplified with the results of DV2CM and DVLogan. 3. Results 3.1. Regional brain kinetics The brain uptake of 2[18F]F-A-85380 was consistent with the known distribution of nAChRs [12]. Higher uptake and slower clearance of the radioligand in the thalamus compared with the other regions were clearly evident. In most subjects, 2[18F]F-A-85380 uptake in the thalamus approached a plateau around 90 min postinjection (93F15.8 min). Cortical regions reached maximal uptake approximately at 60 min postinjection (61F9.4 min), followed by a slow washout, while the cerebellum peaked at around 50 min postinjection (52F9.5 min), followed by a slightly faster clearance than cortical regions. Though presenting the lowest uptake, white matter radioactivity increased slowly throughout the 2-h scan (Fig. 1). 3.2. Plasma kinetics of 2[18F]F-A-85380 A rapid peak of 2.06F0.7 % of ID/100 ml of decaycorrected plasma was followed first by a fast and then a slower exponential clearance (Fig. 2). There was little
Fig. 3. MeanFS.E.M. tissue-to-blood ratios as a function of time for thalamus, cerebellum and frontal cortex (ID 226F36.57 MBq).
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difference observed between venous and arterial plasma radioactivity at 120 min postinjection, with venous plasma 4.2%F0.04 higher than arterial plasma. At 120 min postinjection, 62% of the plasma radioactivity corresponded to unmetabolized 2[18F]F-A-85380 (Fig. 2). Fig. 3 shows the mean ratio of regional brain to metabolite-corrected plasma activity for the thalamus, cerebellum and frontal cortex over the 120-min study period, suggesting that steady state is achieved for cortical
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regions after 90 min postinjection, but not for the thalamus that shows an increasing ratio over the 120-min study. 3.3. Quantification of nAChRs DV values for selected brain regions are shown in Table 1. Comparison of DVsimplified against DVLogan and DV2CM yielded a very high correlation for both frontal cortex (r =.94 and .90 for DVLogan and DV2CM, respectively) and cerebellum (r = .92 and .88 for DVLogan and DV2CM, respectively),
Fig. 4. Analysis of correlation between DVLogan, DV2CM and DVsimplified values derived from 120-min PET scans, in cerebellum, frontal cortex and thalamus. Extrathalamic regions demonstrated high correlation indices. Lower correlations were observed in the thalamus.
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Table 2 Correlation (and P) values for different quantification approaches DVsimplified
SUV
Cerebellum Frontal Ctx Thalamus Cerebellum Frontal Ctx Thalamus
DVLogan
DV2CM
0.92 0.94 0.71 0.18 0.25 0.20
0.88 0.90 0.82 0.44 0.52 0.27
( P b.001) ( P b.001) ( P = .02) ( P = .62) ( P = .48) ( P = .58)
( P b.001) ( P b.001) ( P = .003) ( P = .21) ( P = .12) ( P = .44)
with lower correlation for thalamus (r =.71 and .82 for DVLogan and DV2CM, respectively) (Fig. 4). The correlation between SUVs and the DVLogan and DV2CM was lower and not statistically significant (Table 2). 4. Discussion and conclusion The binding of 2[18F]F-A-85380 as visualized by PET showed the highest uptake in the thalamus, modest uptake in the cerebellum and cortex, and lowest in white matter. Though consistent with the known distribution of nAChR as determined by in vitro and in vivo studies, the uptake in the cerebellum and white matter was greater than expected from previous in vitro human and animal studies of nAChR binding with agents such as [3H]-nicotine and [3H]-epibatidine [41]. While nAChRs are not found in the cerebellum of rodents [42] or Rhesus monkeys [40], significant numbers are present in baboons [27,43] and humans [34,35], suggesting marked species differences in nAChR regional distribution. Time–activity curves for white matter showed progressive accumulation despite a rapid decline in blood levels of 2[18F]F-A-85380, which suggests some specific binding. White matter binding has been previously reported with PET [44,45], and autoradiography using 125I-labelled A-85380 has shown binding in specific white matter tracts [46]. Though the binding to white matter has been attributed to either intraxonal presynaptic receptors undergoing axonal transport [46], axonal postsynaptic receptors of axo-axonal synapses or astrogial receptors [47,48], a full explanation for this apparent specific binding has not been elucidated. Previous reports have shown that 2[18F]F-A-85380 has acceptable radiation dosimetry and no toxic effects at the tracer doses used in PET [33], supporting its potential use in clinical studies. However, the continuous dynamic PET acquisition for 2 h with frequent arterial blood sampling and metabolite correction employed in this study is arduous, time consuming and a hindrance to clinical studies, particularly when the subjects of most interest are either elderly and/or cognitively impaired. A minimum scan duration of 120 min is required for graphical or compartmental analysis of cortical nAChR by 2[18F]F-A-85380, as recently demonstrated [35]. Consequently, we implemented and evaluated simplified methods of quantification, SUV and DVsimplified, against graphical analysis and compartmental modeling. Standardized uptake value is a commonly
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