www.elsevier.com / locate / bres
Short communication
11Age-related reduction of [ C]MDL100,907 binding to central 5-HT
2Areceptors:
PET study in the conscious monkey brain
a a a a b
Takeharu Kakiuchi , Shingo Nishiyama , Kengo Sato , Hiroyuki Ohba , Satoshi Nakanishi ,
a ,
*
Hideo Tsukada
a
Central Research Laboratory, Hamamatsu Photonics K.K., 5000 Hirakuchi, Hamakita, Shizuoka 434-8601, Japan
b
Suzuka University of Medical Science and Technology, Mie 510-0226, Japan
Accepted 22 August 2000
Abstract
Age-related alterations of serotonin (5-hydroxytryptamine; 5-HT) type 2A receptors (5-HT2A) in the living brains of young (6.061.3
11
years old) and aged (19.263.0 years old) monkeys (Macaca mulatta) were evaluated with [ C]MDL100,907 in the conscious state using
high-resolution positron emission tomography (PET). For quantitative analysis of 5-HT2A binding in vivo, PET scan of
11
[ C]MDL100,907 was performed with arterial blood sampling in each animal, and the metabolic-corrected arterial input function was
11
used for Logan graphical analysis. Higher cerebral binding of [ C]MDL100,907 was observed in the hippocampus, cingulate gyrus,
frontal, temporal and occipital cortices, regions known to contain high densities of 5-HT2A, by in vitro assay. Binding was intermediate in
the striatum and thalamus, and lower in the pons and cerebellum in both young and aged monkeys. The age-related decrease in
11
[ C]MDL100,907 binding to 5-HT2A receptors was prominent in the hippocampus, cingulate gyrus, frontal, temporal and occipital
11
cortices, but not in the striatum, thalamus and pons. These observation demonstrated the usefulness of [ C]MDL100,907 as an labeled
compound for assessment of the aging process of the cortical 5-HT2A measured by PET. 2000 Elsevier Science B.V. All rights
reserved.
Theme: Neurotransmitters, modulators, transporters, and receptors
Topic: Serotonin receptors
11
Keywords: Serotonin receptor; [ C]MDL100,907; Aging; Monkey brain; Positron emission tomography
The serotonergic (5-hydroxytryptamine; 5-HT) neuronal Among these, the effect of aging on 5-HT2A has mostly system is widely distributed throughout the brain, and is been addressed in animal models and in human post-involved in mood and behavior, such as emotion, sleep, mortem studies.
pain, feeding, body temperature, sensory functions, motor Positron emission tomography (PET) has been widely and sexual behavior, memory and cognition. Age-related utilized for investigation of the neuroanatomical distri-changes in this neuronal system have been characterized bution of radiolabeled neurotransmitter-specific receptor with respect to the biosynthesis, release, receptor binding, ligands in the living brain. Several radioligands for imag-reuptake and degradation of 5-HT. Age-related decrease in ing of 5-HT2A in the CNS have been developed,
includ-11 18
the density of 5-HT-specific receptor subtypes, 5-HT1A ing [ C]N-methylspiperone [13,34,35], [ F]altanserin 18
[10], 5-HT2A [2,8,11,18,27] and transporter sites of 5-HT [4,20,23] and [ F]setoperone [5–7], and some of these (5-HTT) [1,36] have been reported, all of which were have been applied for evaluation of age-related changes in measured by in vitro autoradiographic binding assays. 5-HT2A receptors. However, these radioligands are not ideal since they show rather low specific-to-nonspecific binding ratio in vivo. Another disadvantage of these *Corresponding author. Tel.: 181-53-586-7111; fax: 1
81-53-586-ligands is their relatively low selectivity for 5-HT
8075. 2A
E-mail address: tsukada@crl.hpk.co.jp (H. Tsukada). receptors with affinity for dopamine D and2 a1-adrenergic
136 T. Kakiuchi et al. / Brain Research 883 (2000) 135 –142
11
receptors [3,17]. [ C]N-Methylspiperone shows a rather ics, Hamamatsu, Japan) with transaxial resolution of 2.6 low uptake ratio of the neocortex to the cerebellum with mm full width at half maximum (FWHM) and a center-to-high affinity for dopamine D2 receptors. In addition, center distance of 3.6 mm [33]. After an overnight fast,
18
fluorine-18 ([ F])-labeled compounds have limit the num- animals were fixed to a the monkey chair with stereotactic ber of repeated studies in the same day, because of the coordinates aligned parallel to the OM line. A cannula was
18
longer half-life (110 min) of [ F] than that of carbon-11 implanted into the posterior tibial vein of the monkey for
11 11
[ C] (20.4 min). administration of [ C]MDL100,907 (100–120 MBq / kg
MDL100,907 [(R)-(1)-4-(1-hydroxy-1-(2,3-dimeth- body weight). Another cannula was put into the femoral oxyphenyl)methyl)-N-2-(4-fluorophynylethyl)piperidine] i- artery of the other leg to obtain arterial blood samples. s a potent and highly selective 5-HT2Areceptor antagonist, PET scan was performed for 91 min with six time frames currently being developed as a potential atypical antipsy- at 10-s intervals, six time frames at 30 s, 12 time frames at chotic drug [24,26]. MDL100,907 binds with subnanomo- 1 min, followed by 25 time frames at 3 min. PET images lar affinity to 5-HT2A receptors (Ki50.2 nM) selectively were generated by summation of image data from 60 to 91 with 300-fold lower affinity for 5-HT2C, 5-HT and 5-HT6 7 min after injection of labeled compounds. Regions of receptors, more than 1000-fold lower for dopamine D , D1 2 interest (ROI) were identified according to MR images of and D4 receptors as compared to 5-HT2A receptors, and each monkey brain, and time–activity curves in ROIs were 100-fold lower affinity fora-adrenergic receptors than that obtained. Arterial blood samples were obtained every 8 s of ketanserine or ritanserin. Recently, MDL100,907 was from 10 to 66 s, followed by 96, 156, 246, 336 s, then 20,
11
labeled with [ C], and its distribution and kinetics were 30, 45, 60, 75 and 90 min after tracer injection. Blood evaluated in the living brains of monkeys [16] and humans samples were centrifuged to separate plasma, weighed and
11
[12]. [ C]MDL100,907 shows relatively moderate lipo- the radioactivity was measured. For metabolite analysis, philicity (log P of 2.79), lower plasma protein binding, and methanol was added to some plasma samples (sample / high specific-to-nonspecific binding ratio [16], suggesting methanol 1:1, v / v), centrifuged and the obtained
super-11
that [ C]MDL100,907 is suitable as a PET ligand for natants were developed by thin layer chromatography non-invasive measurement of 5-HT2A receptors in the (TLC) (AL SIL G / UV, Whatman, Kent, UK) with a living brain. The aim of the present study was to apply this mobile phase of ethylene dichloride / diethyl ether / ethanol /
11
radioligand [ C]MDL100,907 for the evaluation of age- triethylamine (20:20:1:1, v / v). At each sampling time related changes in 5-HT2A receptor binding in the living point for analysis, the ratios of radioactivity in the un-brain of monkeys using high-resolution animal PET [33]. metabolized fraction to that in total plasma (metabolized To minimize the effects of anesthetics on the in vivo plus unmetabolized) were determined using a phos-receptor binding [21,29,31], PET measurements were phoimaging plate (BAS-1500 MAC, Fuji Film Co. Ltd.,
performed in the conscious state. Tokyo, Japan) [29–32].
Five young-adult (6.061.3 years old) and 5 aged The Logan plot directly gives a linear function of the (19.263.0 years old) male rhesus monkeys (Macaca free receptor concentration known as the distribution mulatta) were used for PET measurements. Monkeys were volume based on the following equation [15]:
maintained and handled in accordance with recommenda- T T
tions of the US National Institutes of Health and also the
E
ROI(t) dt / ROI(T )5K
E
Cp(t) dt / ROI(T )1C guidelines of Central Research Laboratory, Hamamatsu0 0
Photonics. The magnetic resonance images (MRI) of all
monkeys were obtained with an MRT-50A / II (0.5T) where ROI(T ) and Cp(T ) represent tissue and arterial (Toshiba, Tokyo, Japan) under anesthesia with pentobarbi- plasma radioactivity, respectively, at time T, K is the slope tal, and the stereotactic coordinates of PET and MRI were and C is the intercept of the y-axis. In reversibly labeled adjusted based on the orbitomeatal (OM) line with a compounds, the Logan plot becomes linear after some time specially designed head holder as previously described with a slope (K ) that is equal to the steady-state
dis-elsewhere [21,28–32]. tribution volume (DV). The ratios of DV in each ROI
11
Positron emitting carbon-11 ( C) was produced by (DV( ROI )) to DV in the cerebellum (DV( CE )) were calcu-14 11
N(p,a) C nuclear reaction using the cyclotron (HM-18, lated to determine the distribution of 5-HT2A receptors in Sumitomo Heavy Industry, Tokyo, Japan) at Hamamatsu the monkey brain. Results are expressed as means6S.D.
11
Photonics PET center and obtained as [ C]CO .2 Comparison between conditions was carried out using the 11
[ C]MDL100,907 was labeled by O-methylation of its paired, two-tailed Student’s t-test, and a probability level nor-compound 3-hydroxy precursor (MDL105,725) with of less than 5% (P,0.05) was considered statistically
11
[ C]methyl iodide [16]. The radioactive purity of significant. 11
Fig. 1 shows typical MRI and PET images of [ C]MDL100,907 used in this study was greater than
11
[ C]MDL100,907 in the brains of young and aged mon-99%, and the specific radioactivity ranged from 54.7 to
keys. PET images were generated by summation of image 98.8 GBq /mmol. PET data were collected on a
Photon-Kakiuchi
et
al
.
/
Brain
Research
883
(2000
)
135
–
142
137
11
138 T. Kakiuchi et al. / Brain Research 883 (2000) 135 –142
pounds into conscious animals. The regional distribution activity curve showed a peak value around 15 min post-11
pattern of [ C]MDL100,907 was highest in the hippocam- injection, followed by a gradual decrease with time (Fig. 11
pus, cingulate gyrus, frontal, temporal and occipital cor- 3). The rank order of uptake of [ C]MDL100,907 in the tices, regions known to contain high densities of 5-HT2A brain of aged monkeys was similar to that of young
11
receptors as determined by in vitro assay [25], with monkeys, while lower uptake of [ C]MDL100,907 was intermediate levels in the striatum and thalamus, and lower observed in aged as compared to young animals (Fig. 3).
11
levels in the pons and cerebellum in both young and aged Age-related reduction of [ C]MDL100,907 uptake was
monkeys (Fig. 1). prominent in the hippocampus, cingulate gyrus, frontal,
In plasma, the curves of total radioactivity showed a temporal and occipital cortices, regions known to contain peak around 30 s post-intravenous bolus injection, and high densities of 5-HT2A receptors by as determined in declined rapidly thereafter (Fig. 2). Metabolite analysis by vitro assay (Fig. 3).
TLC and a phosphoimaging system indicated that each Graphical Logan plot analysis was applied to investigate
11 11
[ C]MDL100,907 was gradually metabolized to very the in vivo binding of [ C]MDL100,907 using the time– polar metabolites, which remained at the origin, and the activity curve each region (Fig. 3) and the
metabolite-11
ratios of radioactivity of unmetabolized [ C]MDL100,907 corrected arterial radioactivity curve as an input function to the total radioactivity (unmetabolized plus metabolized) (Fig. 2). The plot demonstrated linear regression curves in were 35.469.2 and 35.269.0% in young and aged ani- all regions evaluated in both young and aged monkeys,
11
mals, respectively, at 60 min post-injection (Fig. 2B). The suggesting that [ C]MDL100,907 binding to 5-HT2A 11
input function of unmetabolized [ C]MDL100,907 was receptors is reversible (Fig. 4), which was consistent with calculated using the data obtained by correction of total the previous observations in the human brain [12]. As radioactivity relative to the metabolic ratio (Fig. 2A). No summarized in Fig. 5, the binding potential (BP)
de-11
significant changes in the metabolic pattern in plasma and termined as the ratio of DV( ROI ) of [ C]MDL100,907 in 11
the resulting input function of [ C]MDL100,907 were each region against that in the cerebellum (DV( CE )), a observed between young and aged animals (Fig. 2). reference region with less 5-HT2A receptors, was
corre-11
After intravenous injection, [ C]MDL100,907 was lated with 5-HT2A receptor density (Bmax) as measured by rapidly taken up into the brain, showing high uptake in the in vitro assay [25]. The age-related reduction of BP was hippocampus, cingulate gyrus, frontal, temporal and oc- prominent in the cingulate gyrus (73.1% of young ani-cipital cortices, with low levels in the pons and cerebellum mals), hippocampus (77.6%), occipital (76.9%), temporal
11
(Fig. 3). The time–activity curves of [ C]MDL100,907 in (77.2%) and frontal (77.5%) cortices, all of which are the regions with high densities of 5-HT2A receptors known to contain high densities of 5-HT2A receptors as gradually increased with time during the scan until 91 min determined by in vitro assay. In contrast, no significant after injection (Fig. 3), while those in the striatum and reductions of BP were observed in the striatum, thalamus thalamus peaked at 20–30 min post-injection. In the and pons (Figs. 4 and 5).
cerebellum with low 5-HT2A receptor density, the time– In the present study, we first evaluated the age-related
11
Fig. 2. Time–activity curves of [ C]MDL100,907 in the plasma of young and aged monkeys following intravenous injection. The time–activity curve of
11
11
Fig. 3. Time–activity curves of [ C]MDL100,907 in the brains of young (A) and aged (B) conscious monkeys. PET scans were performed as shown in the legend of Fig. 1. Regions of interest (ROIs) were identified according to MRI of each animal. Radioactivity uptake in each region was normalized to an injected dose of 1 GBq and body weight of 7 kg.
alterations of 5-HT2A receptor binding in the living brains temporal and occipital cortices, hippocampus and cingulate of nonhuman primates in the conscious state using gyrus, all of which are rich in 5-HT2A receptors.
11
[ C]MDL100,907 and high-resolution animal PET. Age- For quantitative analysis of 5-HT2A receptor binding in 11
related reduction of [ C]MDL100,907 binding in vivo in vivo with graphical analysis, the cerebellum was used as the conscious monkey brain was prominent in the frontal, reference based on the following considerations: (1) the
11
Fig. 4. Logan plot analysis of [ C]MDL100,907 in the brains of young (A) and aged (B) conscious monkeys. Analysis was performed on the regional
11
140 T. Kakiuchi et al. / Brain Research 883 (2000) 135 –142
significant cerebral atrophic alterations compared to those of young animals. In addition, although MR-derived regional tissue correction factors indicated a significant difference in cortical brain volume between young and aged animals, correction for the effects of atrophy on PET data accounted for less than 5% [20]. Thus, the effect of atrophy was small relative to the large change in 5-HT2A receptor availability in the monkey brain with aging as
11
measured by [ C]MDL100,907.
As mentioned previously, age-related changes in the 5-HT neuronal system have been characterized with re-spect to the biosynthesis, release, receptor binding, reup-take and degradation of 5-HT. This was reported to be related to a mild impairment of memory in the elderly, not associated with dementia [14]. More recently, age-related memory impairment was defined as age-associated mem-ory impairment or AAMI [9]. The serotonergic neuronal system has been considered important for learning and
11 memory based on the effects of serotonergic drugs on
Fig. 5. Age-related changes in [ C]MDL100,907 binding to 5-HT2A
these functions in animals and in humans with cognitive receptors in the conscious monkey brain. The ratios of DV in each ROI
(DV( ROI )) to DV in the cerebellum (DV( CE )) were calculated from data impairment (for review, see Ref. [19]). The relevance of shown in Fig. 4 for Logan binding potential. Data represent means6S.D. loss of 5-HT receptors in the age-related impairment of
2A for five animals per age group. * P,0.05 vs. young animals.
memory function is, however, still unclear, partly because of limitations of postmortem studies. PET can be used for cerebellar structure is known to contain few 5-HT2A analysis of 5-HT2A receptors in the living brain, thus receptors in primates [25]; and (2) the time–activity curve obviating such limitations. In addition to the age-related
11
of [ C]MDL100,907 in the cerebellum is not affected by alterations, in vivo imaging technology of 5-HT2Areceptor saturating doses of ketanserine, a selective 5-HT antago-2 functions will be useful for diagnosis and treatment of nist [16]. In addition, only slight differences were detected several neuropsychiatric diseases including major depres-in the time–activity curves depres-in the cerebellum between sion, psychotic disorders, dementia and drug abuse, in young and aged animals, suggesting that the cerebellum which abnormalities of 5-HT2 receptors have been pro-might be a reasonable region for quantitative analysis of posed to play a variety of roles. In the present study,
11
5-HT2A receptor binding in vivo using PET. The age- [ C]MDL100,907 demonstrated higher binding through-related reduction of rCBF might, in part, contribute to the out the neocortical regions, with lower levels of binding in
11
lower cortical uptake of [ C]MDL100,907 in the aged the striatum, thalamus and cerebellum, consistent with the monkey brain. Our preliminary results demonstrated that cortical distribution of 5-HT2A receptors as previously the rCBF level in the cortex was significantly lower in determined by radioligand binding in vitro [25] as well as aged monkeys (37.166.7 ml / 100 g tissue / min) than in mRNA level [22]. Furthermore, an age-related decrease in young animals (54.667.4 ml / 100 g tissue / min) (Noda, 5-HT2A receptor binding in vivo was detected especially Tsukada et al., unpublished observation). However, the in the neocortex, consistent with the results of previous reduced rCBF seems unlikely to be responsible for the in vitro [2,8,11,18,27] and in vivo [5,13,20,35] studies. lower specific binding of the ligand in aged animals. The Taken together, these observations suggested that
11
DV obtained by Logan plot analysis is a linear function of [ C]MDL100,907, which shows highly specific binding to free receptor concentration and is not dependent on rCBF 5-HT2A receptors, should be suitable as a radiolabeled since the variables containing blood flow cancel in the ligand for non-invasive PET studies in the living brain. ratio of the transport constant, K /k (K is the plasma-to-1 2 1
tissue transport constant and k2 is the tissue-to-plasma transport constant) [15]. Another possible explanation for
the lower uptake in aged animals might be the altered Acknowledgements 11
metabolic rate of [ C]MDL100,907 to in plasma.
How-ever, this is also unlikely, because no significant differ- We gratefully acknowledge the excellent technical assis-ences were observed in the plasma metabolism of tances provided by Yoshihiro Murakami for preparation of
11
[19] W. McEntee, T.H. Crook, Serotonin, memory, and aging brain, References
Psychopharmacology 103 (1991) 143–149.
[20] C.C. Meltzer, G. Smith, J.C. Price, C.F. Reynolds III, C.A. Mathis,
3
[1] R.C. Arora, A. Gulati, J.W. Crayton, Aging and [ H]paroxetine
P. Greer, B. Lopresti, M.A. Mintun, B.G. Pollock, D. Ben-Eliezer, binding in rat brain: effect of imipramine and tetrahydroacridine,
M.N. Cantwell, W. Kaye, S.T. DeKosky, Reduced binding of
Life Sci. 52 (1993) 1767–1775. 18
[ F]altanserin to serotonin type 2A receptors in aging: persistence [2] B. Arranz, A. Eriksson, E. Mellerup, P. Plenge, J. Marcusson, Effect
of effect after partial volume correction, Brain Res. 813 (1998) of aging in human cortical pre and postsynaptic serotonin binding
167–171. sites, Brain Res. 620 (1993) 163–166.
[21] H. Onoe, O. Inoue, K. Suzuki, H. Tsukada, T. Ito, N. Mataga, Y. [3] R.J. Baldessarini, N.S. Kula, A. Campbell, V. Bakthavachalam, J.
11
Watanabe, Ketamine increases the striatal N- C-methylspiperone Yuan, J.L. Neumeyer, Prolonged D2 antidopaminergic activity of
binding in vivo: positron emission tomography study using con-alkylating and noncon-alkylating derivatives of spiperone in rat brain,
scious rhesus monkey, Brain Res. 663 (1994) 191–198. Mol. Pharmacol. 42 (1992) 856–863.
[22] M. Pompeiano, J.M. Palacios, G. Mengod, Distribution of the [4] F. Biver, S. Goldman, A. Luxen, M. Monclus, M. Forestrine, J.
serotonin HT receptor family mRNAs: comparison between 5-Mendlewicz, F. Lotstra, Multicompartmental study of fluorine-18 2
HT and 5-HT receptors, Mol. Brain Res. 23 (1994) 163–178. altanserin binding to brain 5-HT2 receptors in humans using 2A 2C
[23] B. Sadzot, C. Lemaire, P. Maquet, E. Salmon, A. Plenevaux, C. positron emission tomography, Eur. J. Nucl. Med. 21 (1994) 937–
946. Degueldre, J. Hermanne, M. Guillaume, R. Cantineau, D. Comar, G.
[5] J. Blin, J.C. Baron, B. Dubois, C. Crouzel, M. Fiorelli, D. Attar- Franck, Serotonin 5-HT receptor imaging in the human brain using2
Levy, B. Pillon, D. Fournier, M. Vidailhet, Y. Agid, Loss of brain positron emission tomography and a new radioligand,
18
5-HT receptors in Alzheimer’s disease, Brain 116 (1993) 497–510.2 [ F]altanserin: results in young normal controls, J. Cereb. Blood [6] J. Blin, S. Pappata, M. Kiyosawa, C. Crouzel, J.C. Baron, Flow Metab. 15 (1995) 787–797.
18
[ F]setoperone: a new high-affinity ligand for positron emission [24] C.J. Schmidt, G.M. Fadayel, The selective 5-HT2Areceptor antago-tomography study of serotonin-2 receptors in baboon brain in vivo, nist, NDL100907, increases dopamine efflux in the prefrontal cortex Eur. J. Pharmacol. 147 (1988) 73–82. of the rat, J. Pharmacol. Exp. Ther. 273 (1995) 273–279. [7] J. Blin, G. Sette, M. Fiorelli, O. Bletry, J.L. Elghozi, C. Crouzel, [25] A. Schotte, J.M. Maloteaux, P.M. Laduron, Characterization and
J.C. Baron, A method for the in vivo investigation of the serotoner- regional distribution of serotonin S -receptors in human brain, Brain2
gic 5-HT2 receptors in the human cerebral cortex using positron Res. 276 (1983) 231–235.
18
emission tomography and F-labeled setoperone, J. Neurochem. 54 [26] S.M. Sorensen, J.H. Kehne, G.M. Fadayel, T.M. Humphreys, H.J. (1990) 1744–1754. Ketteler, C.K. Sullivan, V.L. Taylor, C.J. Schmidt, Characterization [8] S. Cheetham, M. Crompton, C. Katona, R. Horton, Brain 5-HT2 of the 5-HT receptor antagonist MDL100907 as a putative atypical2
receptor binding sites in depressed suicide victims, Brain Res. 443 antipsychotic: behavioral, electrophysiological and neurochemical (1988) 272–280. studies, J. Pharmacol. Exp. Ther. 266 (1993) 684–691.
[9] T. Crook, R.T. Bartus, S.H. Ferris, P. Whitehouse, G.D. Cohen, S. [27] D. Sparks, Aging and Alzheimer’s disease. Altered cortical Gershon, Age-associated memory impairment. Proposed diagnostic serotonergic binding, Arch. Neurol. 46 (1989) 138–140.
criteria and measures of clinical change: report of a National [28] H. Takechi, H. Onoe, K. Imamura, K. Onoe, T. Kakiuchi, S. Institute of Health work group, Dev. Neuropsychol. 2 (1986) 261– Nishiyama, E. Yoshikawa, S. Mori, T. Kosugi, H. Okada, H.
276. Tsukada, Y. Watanabe, Brain activation study by use of positron
[10] K.A. Dillon, R. Gross-Isseroff, M. Isreli, A. Biegon, Autoradio- emission tomography in unanesthetized monkey, Neurosci. Lett. 182 graphic analysis of serotonin 5HT1Areceptor binding in the human (1994) 279–282.
brain postmortem: effects of age and alcohol, Brain Res. 554 (1991) [29] H. Tsukada, N. Harada, S. Nishiyama, H. Ohba, K. Sato, D.
11
56–64. Fukumoto, T. Kakiuchi, Ketamine decreased striatal [ C]raclopride
[11] R. Gross-Isseroff, D. Salama, M. Isreli, A. Biegon, Autoradiographic binding with no alterations in static dopamine concentrations in the
3
analysis of [ H]ketanserine binding in the human brain postmortem: striatal extracellular fluid in the monkey brain: multi-parametric PET effect of suicide, Brain Res. 507 (1990) 208–215. studies combined with microdialysis analysis, Synapse 37 (2000) [12] H. Ito, S. Nyberg, C. Halldin, C. Lundkvist, L. Farde, PET imaging 95–103.
11
of central 5-HT2Areceptors with [ C]MDL100,907, J. Nucl. Med. [30] H. Tsukada, S. Nishiyama, T. Kakiuchi, H. Ohba, K. Sato, N. 39 (1998) 208–214. Harada, Is synaptic dopamine concentration the exclusive factor
11
[13] M. Iyo, T. Yamasaki, The detection of age-related decrease of which alters the in vivo binding of [ C]raclopride? PET studies dopamine D , D1 2 and serotonin 5-HT2 receptors in living brain, combined with microdialysis in conscious monkeys, Brain Res. 841 Prog. Neuro-Psychopharmacol. Biol. Psychiatr. 17 (1993) 415–421. (1999) 160–169.
[14] V.A. Kral, Senescent forgetfulness: benign and malignant, J. Can. [31] H. Tsukada, S. Nishiyama, T. Kakiuchi, H. Ohba, K. Sato, N. Med. Assoc. 86 (1962) 257–260. Harada, S. Nakanishi, Isoflurane anesthesia enhances the inhibitory [15] J. Logan, J. Fowler, N. Volkow, A. Wolf, S. Dewey, D. Schleyer, R. effects of cocaine and GBR12909 on dopamine transporter: PET Macgregor, R. Hitzemann, B. Bendriem, S. Gatley, D. Christman, studies in combination with microdialysis in the monkey brain, Graphical analysis of reversible radioligand binding from time– Brain Res. 849 (1999) 85–96.
11
activity measurements applied to N- C-methyl-(2)-cocaine PET [32] H. Tsukada, N. Harada, S. Nishiyama, H. Ohba, T. Kakiuchi, Dose studies in human subjects, J. Neurochem. 10 (1990) 740–747. response and duration effects of acute administrations of cocaine [16] C. Lundkvist, C. Halldin, N. Ginovart, S. Nyberg, C.G. Swahn, A.A. and GBR12909 on dopamine synthesis and transporter in the
11
Carr, F. Brunner, L. Farde, [ C]MDL100,907, a radioligand for conscious monkey brain: PET studies combined with microdialysis, selective imaging of 5-HT2A receptors with positron emission Brain Res. 860 (2000) 141–148.
tomography, Life Sci. 58 (1996) PL187–PL192. [33] M. Watanabe, H. Okada, K. Shimizu, T. Omura, E. Yoshikawa, T. [17] R. Lyon, M. Titeler, J. Frost, P. Whitehouse, D. Wong, H.N. Wager, Kosugi, S. Mori, T. Yamashita, A high resolution animal PET
3
R. Dannals, J. Links, M. Kuhar, H-3-N-methylspiperone labels D2 scanner using compact PS-PMT detectors, IEEE Trans. Nucl. Sci. dopamine in basal ganglia and S2 serotonin receptors in cerebral 44 (1997) 1277–1282.
cortex, J. Neurosci. 6 (1986) 2941–2949. [34] G.J. Wong, N.D. Volkow, J. Logan, J.S. Fowler, D. Schlyer, R.R. [18] J. Marcusson, D. Morgan, B. Winblad, C. Finch, Serotonin-2 binding MacGregor, R.J. Hitzemann, A. Gjedde, A.P. Wolf, Serotonin 5-HT2
142 T. Kakiuchi et al. / Brain Research 883 (2000) 135 –142
![Fig. 1. MRI and PET images of [ C]MDL100,907 in the brains of young (A) and aged (B) conscious monkeys](https://thumb-ap.123doks.com/thumbv2/123dok/3139127.1382715/3.792.49.734.87.467/fig-mri-pet-images-brains-young-conscious-monkeys.webp)
![Fig. 2. Time–activity curves of [ C]MDL100,907 in the plasma of young and aged monkeys following intravenous injection](https://thumb-ap.123doks.com/thumbv2/123dok/3139127.1382715/4.612.140.456.483.693/time-activity-curves-plasma-monkeys-following-intravenous-injection.webp)
![Fig. 3. Time–activity curves of [ C]MDL100,907 in the brains of young (A) and aged (B) conscious monkeys](https://thumb-ap.123doks.com/thumbv2/123dok/3139127.1382715/5.612.152.440.454.658/fig-time-activity-curves-brains-young-conscious-monkeys.webp)
![Fig. 5. Age-related changes in [ C]MDL100,907 binding to 5-HT11receptors in the conscious monkey brain](https://thumb-ap.123doks.com/thumbv2/123dok/3139127.1382715/6.612.46.286.61.272/fig-related-changes-binding-receptors-conscious-monkey-brain.webp)
