Comparison of Dopamine D3 and D2 Receptor Occupancies by a Single Dose of Blonanserin in Healthy Subjects: A Positron Emission Tomography Study With [11C]-(+)-PHNO

Comparison of Dopamine D3 and D2 Receptor Occupancies by a Single Dose of Blonanserin in Healthy... Background: Blockade of D receptor, a member of the dopamine D-like receptor family, has been suggested as a possible 3 2 medication for schizophrenia. Blonanserin has high affinity in vitro for D as well as D receptors. We investigated whether 3 2 a single dose of 12  mg blonanserin, which was within the daily clinical dose range (i.e., 8–24  mg) for the treatment of schizophrenia, occupies D as well as D receptors in healthy subjects. 3 2 Methods: Six healthy males (mean 35.7 ± 7.6 years) received 2 positron emission tomography scans, the first prior to taking blonanserin, and the second 2 hours after the administration of a single dose of 12  mg blonanserin. Dopamine receptor occupancies by blonanserin were evaluated by [C]-(+)-PHNO. Results: Occupancy of each region by 12 mg blonanserin was: caudate (range 64.3%–81.5%; mean ± SD , 74.3 ± 5.6%), putamen (range 60.4%–84.3%; mean± SD, 73.3% ± 8.2%), ventral striatum (range 40.1%–88.2%; mean ± SD , 60.8% ± 17.1%), globus pallidus (range 65.8%–87.6%; mean± SD, 75.7% ± 8.6%), and substantia nigra (range 56.0%–88.7%; mean ± SD, 72.4% ± 11.0%). Correlation analysis between plasma concentration of blonanserin and receptor occupancy in D -rich (caudate and putamen) and D -rich 2 3 (globus pallidus and substantia nigra) regions showed that EC for D -rich region was 0.39 ng/mL (r = 0.43) and EC for D -rich 50 2 50 3 region was 0.40 ng/mL (r= 0.79). Conclusions: A single dose of 12 mg blonanserin occupied D receptor to the same degree as D receptor in vivo. Our results 3 2 were consistent with previous studies that reported that some of the pharmacological effect of blonanserin is mediated via D receptor antagonism. Keywords: D receptor, D receptor, blonanserin, positron emission tomography 2 3 Received: May 10, 2017; Revised: December 14, 2017; Accepted: January 10, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 522 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/522/4807374 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Tateno et al. | 523 Significance Statement The focus of this study was on the occupancies of blonanserin for both dopamine D and D receptors in vivo. This study found 2 3 that 12 mg blonanserin occupied D -rich region (i.e., 75.7% in globus pallidus and 72.4% in substantia nigra) as much as -ric D h 3 2 region (i.e., 74.3% in caudate and 73.3% in putamen) in healthy volunteers. Correlation analysis between the plasma concentra- tion of blonanserin and receptor occupancy showed that the EC values of D -rich regions and D-rich regions are very similar 50 2 3 (0.39  ng/mL, r= 0.43 and 0.40  ng/mL, r= 0.79). Our results indicated the possibility that some of the pharmacological effect of blonanserin is mediated via D receptor antagonism. Introduction The mechanism of the antipsychotic effect of neuroleptics 9–10) similarly to a D-rich region (i.e., striatum) in rat brain, mainly focuses on the antagonism of D receptor (Seeman, 2002). while risperidone, olanzapine, and aripiprazole did not (Baba D receptor antagonism can also induce some adverse effects et al., 2008). Blonanserin demonstrated efficacy against cogni- (e.g., Parkinsonism, hyperprolactinemia), and therefore many tive impairment induced by phencyclidine by inhibiting both researchers have been studying the effects of antipsychotics on dopamine D and serotonin 5-HT receptors in rat (Hida et al., 3 2A the dopaminergic system and other monoaminergic systems, 2015). Thus, blonanserin has been thought to have D antag- and also the association between pharmacological treatment onism identical to D and clinical efficacy by D receptors. 2 3 and the change of monoaminergic systems in vivo. However, there has been no study of the evaluation of D occu- Dopamine D receptor, a member of the dopamine D-like pancy by blonanserin. 3 2 receptor family, localizes in the limbic area and coexists with D In this study, we investigated whether a clinical dose of blo- receptors in the substantia nigra as well as in many other areas nanserin occupies D receptors as well as D receptors in healthy 3 2 in human brain. D receptor has similarities to other members of subjects. the D -like receptor family, but D receptor has very high affinity 2 3 for dopamine and modulates dopamine release as an autore- Methods ceptor (Gross and Drescher, 2012). Some previous studies have reported that selective D receptor antagonists might increase Subjects the extracellular dopamine concentrations in the medial pre- Six healthy male volunteers (range 27–46  years; mean ± SD , frontal cortex (Gross and Drescher, 2012) and are also able to 35.7 ± 7.6) were enrolled. None had a history of present or past increase acetylcholine (Kuroki et  al., 1999). These pharmaco- psychiatric, neurological, or somatic disorders, or alcohol or logical studies and studies of rodent D receptors have suggested substance-related problems. After thorough explanation of the that blockade of D receptor might represent a new treatment study, written informed consent was obtained from all partici- mechanism for schizophrenia (Gross et al., 2013). pants. This study was approved by the review board of Nippon Many atypical antipsychotics and some typical antipsychot- Medical School Hospital, Tokyo, Japan. ics have high affinities for both D and D receptors (Girgis et al., 2 3 2011). Recent technological progress has allowed us to visualize 11 Study Design the distribution of D receptors in vivo. [ C]-(+)-PHNO is a D /D 3 3 2 agonist radioligand for positron emission tomography (PET) with This study was designed as a single administration, open- preferential in vivo selectivity for dopamine D over D receptor 3 2 label protocol. Each subject underwent 2 PET scans, the first (Willeit et al., 2006Gino ; vart et al., 2007). Almost all of the sig- prior to taking blonanserin, and the second 2 hours after being nal of [ C]-(+)-PHNO in both caudate and putamen represented administered of 12  mg blonanserin, which targeted the time- D receptor sites, while up to 100% of the signal in substantia to-maximum blood concentration of blonanserin (Saruwatari nigra, 67% in globus pallidus, and 26% in ventral striatum repre- et al., 2010). sented D receptor sites (Searle et al., 2010). An in vitro affinity study suggested that antipsychotics would occupy D receptors PET Procedures as much as D receptors, although antipsychotics reportedly occupied D receptors moderately less than D receptors (Girgis PET scans were carried out with Eminence SET-3000GCT-X 3 2 et  al., 2011), and a PET study with [C]-(+)-PHNO reported that (Shimadzu Corp) to measure regional brain radioactivity. This antipsychotics (i.e., clozapine, risperidone, olanzapine) did not scanner provides 99 sections with an axial field of view of decrease or even increased the in vivo nondisplaceable binding 26.0 cm. Spatial resolution was 3.45 mm in-plane and 3.72 mm potential (BP ) of D receptors in human brain (Graff-Guerrero axially full-width at half-maximum. A head fixation device was ND 3 et al., 2009). Another study also reported that chronically admin- used during the scans. A 15-min transmission scan was done to istered antipsychotics (i.e., clozapine, olanzapine, and haloperi- 137 correct for attenuation using a Cs source. Dynamic PET scan dol) showed lower selectivity for D compared with D receptors 3 2 was performed for 90 min (1 min× 15, 5 min × 15) after i.v. bolus ex vivo than in vitro in rat brain (McCormick et al., 2010). 11 injection of [ C]-(+)-PHNO. Injected radioactivity was 196.4 to Blonanserin is an atypical antipsychotic, but unlike other 385.0 MBq (348.8 ± 64.2 (mean ± SD MBq) for drug-free condition; atypical antipsychotics, the binding affinity for D receptors 339.8 ± 70.2 MBq for blonanserin condition). The injected mass of (Ki = 0.284 nM) is slightly higher than that for 5-HT receptors 2A [ C]-(+)-PHNO was 1.9  – 2.5 μg (2.2 ± 0.3 μg for drug-free condi- (Ki = 0.64  nM) in vitro (Murasaki et  al., 2008). Blonanserin has tion; 2.4 ± 0.1 μg for blonanserin condition). Specific radioactiv- high in vitro affinity for dopamine D receptor (Ki = 0.277  nM), 3 ity was 41.7  – 95.4 GBq/µmol (77.7 ± 7.5 GBq/µmol for drug-free similar to that for D receptor (Ki= 0.284 nM) (Baba et al., 2008). condition; 77.9 ± 7.5 GBq/µmol for blonanserin condition) at the Blonanserin occupied a D-rich region (i.e., cerebellum lobe 3 time of injection. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/522/4807374 by Ed 'DeepDyve' Gillespie user on 21 June 2018 524 | International Journal of Neuropsychopharmacology, 2018 receptor occupancy between in vitro and in vivo studies has MRI Procedures been reported (Graff-Guerrero et  al., 2010McCormic ; k et  al., Magnetic resonance (MR) images of the brain were acquired 2010), correlations between plasma concentration and recep- with 1.5T MR imaging, Intera 1.5T Achieve Nova (Philips Medical tor occupancy were examined. Systems) as proton density image (echo time = 17 msec; repe- tition time= 6000 msec; field of view = 22  cm, 2-dimensional, Results 256 × 256; slice thickness = 2  mm; number of excitations = 2). These images were used for analysis of the PET scans. Five subjects each completed two 90-min PET scans with [ C]-(+)-PHNO. One subject provided partial data: the first PET scan (drug-free condition) was stopped at 70  min because of Measurement of Plasma Concentration of the subject’s anxiety. We then included both conditions of 0 to Blonanserin 70 min PET data of this subject. Venous blood samples were taken just before second PET scans Figure  1 shows BP of each ROI in each condition. Average ND (2 hours after taking 12 mg blonanserin), collected in tubes con- BP in drug-free condition was as follows: caudate (BP range ND ND taining EDTA-2Na, and centrifuged at 3000 rpm for 10 min at 4ºC. 1.04–1.68; mean ± SD, 1.53 ± 0.24), putamen (BP range 1.28–2.06; ND Separated plasma samples were stored at -80ºC until analysis. 1.82 ± 0.29), ventral striatum (BP range 1.59–2.85; 2.40± 0.43), ND Plasma concentration was measured by validated method using globus pallidus (BP range 1.56–2.68; 2.16± 0.40), and substantia ND high-performance liquid chromatography-tandem mass spec- nigra (BP range 0.96–1.42; 1.06± 0.17). Average BP in blonan- ND ND trometry with a target lower quantification limit of 0.001 ng/mL serin condition was as follows: caudate (BP range 0.27–0.60; ND (Sekisui Medical Co., Ltd.). 0.40 ± 0.12), putamen (BP range 0.20–0.77; 0.50± 0.19), ventral ND striatum (BP range 0.19–1.70; 0.99± 0.52), globus pallidus (BP ND ND range 0.19–0.91; 0.54± 0.24), and substantia nigra (BP range ND Data Analysis 0.11–0.47; 0.30 ± 0.13). The average level of receptor occupancy by a single dose of blonanserin 12  mg was as follows: cau- MR images were co-registered to summated PET images date (range 64.3–81.5; 74.3± 5.6%), putamen (range 60.4–84.3; with the mutual information algorithm using PMOD (v - er 73.3 ± 8.2%), ventral striatum (range 40.1–88.2; 60.8 ± 17.1%), glo- sion 3.4; PMOD Technologies Ltd). Regions of interest (ROIs) bus pallidus (range 65.8–87.6; 75.7 ± 8.6%), and substantia nigra were defined for the caudate, putamen, ventral striatum, glo- (range 56.0–88.7; 72.4± 11.0%) (Table 1). bus pallidus, and substantia nigra, and were drawn manu- The average drug concentration of blonanserin was 1.49 ± 0.88 ally in accordance with Tziortzi’s study (Tziortzi et al., 2011). (mean ± SD) ng/mL (range 0.58–2.90). Correlations between We defined the caudate and putamen as D-rich regions and plasma concentration of blonanserin and receptor occupancy in the substantia nigra and globus pallidus as D -rich regions, D -rich and D -rich ROI are shown in Figure 2. EC was 0.39 ng/ according to Searle’s study (Searle et  al., 2010). ROIs were 2 3 50 mL (df = 11, r = 0.43) for D-rich region and 0.40  ng/mL (df= 11, drawn manually on overlaid summated PET and co-r egistered r = 0.79) for D -rich region. MR images of each subject. By matching the targeted frame to the average of the first 10 frames (i.e., 0–10 minutes), motion corrections were conducted in 3 scans of 2 subjects because Discussion of head movements. In this study, we examined the receptor occupancies in both D - Quantitative estimate of binding of [C]-(+)-PHNO was per- rich and D -rich regions by a single dose of 12 mg blonanserin formed using a simplified reference tissue model (Lammertsma using [ C]-(+)-PHNO PET. A  single dose of 12  mg blonanserin and Hume, 1996), with the cerebellar cortex as reference region. occupied dopamine receptors in D-rich regions (i.e., substantia This model has been validated to reliably estimate BP , which ND nigra, globus pallidus) as much as in D -rich regions (i.e., cau- compares the concentration of radioligand in the receptor- date, putamen). Receptor occupancy in the striatum by 12  mg rich region with the receptor-free region (Innis et al., 2007), for blonanserin (74.3% for caudate and 73.3% for putamen) was [ C]-(+)-PHNO (Ginovart et al., 2007). almost the same as by [ C]raclopride (68.5% for the striatum as Receptor occupancy by drugs was calculated by the following calculated based on our previous data; Tateno et al., 2013). Thus, equation: a single dose of 12 mg blonanserin, within the clinical daily dose Occupancy () %/ =- BP BP BP ´ 100, () NDbase NDdrug NDbase range for the treatment of schizophrenia, occupied D receptors to approximately the same extent as D receptors. Thus, this is where occupancy is the receptor occupancy, BP is BP NDbase ND the first study to show that this dopamine antagonist occupied under drug-free condition, and BP is BP under blonan- NDdrug ND both D and D receptors at about the same levels. 2 3 serin condition. Since dopaminergic hypofunction in the prefrontal cortex has We used a 1-site binding model, the same as a previous study been implicated in the pathogenesis of negative symptoms (Davis (Graff-Guerrero et  al., 2010). The relationship between plasma et al., 1991) and cognitive dysfunctions of schizophrenia (Sawaguchi, concentration and receptor occupancy was shown by the follow- 2000), D receptor antagonism might improve the negative symp- ing equation: toms and cognitive deficits of schizophrenia. Animal studies have Occupancy () %/ =´ E C E () C+C ´ 100, reported that blonanserin showed cognitive efficacy via D recep- max50 tor antagonism and that it had a beneficial effect on prefrontal dopamine transmission (Gross et  al., 2013Nakajima et  ; al., 2013; where C is the plasma concentration of drug, E is the max maximum occupancy, and EC is the plasma concentra- Hida et  al., 2015). Other clinical studies showed that blonanserin induced improvements in verbal fluency and executive function tion required to achieve 50% occupancy (Takano et al., 2006; Graff-Guerrero et  al., 2010). E was fixed at 1 and EC > 0, (Tenjin et  al., 2012; Hori et  al., 2014), which might be related to max 50 the effect of this antipsychotic on dopamine transmission pre- the same as in previous occupancy studies (Takano et  al., 2006; Graff-Guerrero et  al., 2010). Since discrepancy of D frontal cortex function. It has also been reported that functional Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/522/4807374 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Tateno et al. | 525 Figure 1. Binding potential (BP ) of [ C]-(+)-PHNO for every region of interest before and after taking 12 mg blonanserin. Filled circles represent the subject with 70-min ND PET scans. Table  1. Average Binding Potential and Occupancy of Dopamine that a single dose of 12  mg blonanserin antagonizes D receptor Receptors in Each Region as much as D receptor, as has been indicated by previous studies (Baba et al., 2015), and therefore further study regarding what per - Region of Interest Drug-free Blonanserin Occupancy (%) centage of D occupancy by antipsychotics might improve cogni- tion could be beneficial for treatment strategies of schizophrenia. Caudate 1.53 ± 0.24 0.40 ± 0.12 74.3 ± 5.6 Putamen 1.82 ± 0.29 0.50 ± 0.20 73.3 ± 8.2 The mechanism underlying the discrepancies between in Globus pallidus 2.16 ± 0.40 0.54 ± 0.24 75.7 ± 8.6 vitro and in vivo bindings of several antipsychotics to dopamine Ventral striatum 2.40 ± 0.43 0.99 ± 0.52 60.8 ± 17.1 D receptors (Graff-Guerrero et al., 2010 McCormic ; k et al., 2010) is Substantia nigra 1.06 ± 0.17 0.30 ± 0.13 72.4 ± 11.0 still unclear. However, several explanations have been proposed. Girgis presented the upregulation scenario (Girgis et  al., 2011). The study in baboons demonstrated binding of both D and D 2 3 connectivity between the prefrontal cortex and salience/executive receptors by an acute dose of haloperidol (haloperidol: 70% of control networks negatively associated with midbrain D receptor putamen and 61% of globus pallidus, clozapine: 43% of putamen availability (Cole et  al., 2011). Many PET studies have suggested and 21% of globus pallidus). Girgis further suggested that upreg- that around 70% to 80% D receptor occupancy in the striatum is ulation of D receptor induced by chronic use of antipsychot- required for an antipsychotic effect with a lower risk of extrap - yr ics might affect the discrepancy between the results of in vitro amidal adverse effects (Farde et  al., 1992Nor ; dström et  al., 1993; affinity study and in vivo PET study (Girgis et al., 2011). Our study Kapur et al., 2000). Previous studies showed that 150 mg of ABT-925, participants were healthy volunteers with a single administra- a selective D receptor antagonist, possibly improves positive and tion, and our result was consistent with this scenario. Another negative symptoms of schizophrenia, and that it occupied about explanation could be the influence of endogenous dopamine. 30% of D receptors in substantia nigra and globus pallidus (Graff- Schotte reported that the D /D potency ratios of antipsychotics 2 3 Guerrero et al., 2010Bhathena et  ; al., 2013). A recent study showed (i.e., clozapine, olanzapine, risperidone, haloperidol) in vivo were that a clinical dose of cariprazine, a D -preferring dual D/D recep- 2 to 10 times higher than those of in vitro competitive binding 3 3 2 tor partial agonist for the treatment of schizophrenia, occupied at experiments (Schotte et al., 1996), and they suggested that this least 76% of D receptors, along with 45% of D receptors (Girgis effect was due to the in vivo inhibitory influence of endogenous 3 2 et  al., 2016). However, the adequate degree of D receptor occu- dopamine. It has been suggested that antipsychotics inhibit D 3 2 pancy for an antipsychotic effect or improvement of motivation and D receptors in a dose-dependent manner, but the relation- and/or cognition has been unclear. Our result provided evidence ship between drug concentration and inhibitory effect differed Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/522/4807374 by Ed 'DeepDyve' Gillespie user on 21 June 2018 526 | International Journal of Neuropsychopharmacology, 2018 Figure 2. Correlation between receptor occupancy in D -rich (caudate and putamen) and D -rich (globus pallidus and substantia nigra) regions with [ C]-(+)-PHNO and 2 3 plasma concentration of 12 mg blonanserin. Filled circles represent the subject with 70-min PET scans. according to the respective antipsychotics. Tadori reported that Megumi Hongo, and Minoru Sakurai for their assistance in most antipsychotics at clinical dose sufficiently antagonize D performing the PET experiments and MRI scanning, and receptor signals but not D receptor signals, while blonanserin, Michiyo Tamura for her help as clinical research coordin- haloperidol, and fluphenazine inhibit D receptor at a similar ator (Clinical Imaging Center for Healthcare, Nippon Medical level to D receptor (Tadori et  al., 2011). Their study suggested School, Tokyo, Japan). that a clinical dose of antipsychotics, except for blonanserin, haloperidol, and fluphenazine, preferentially inhibits D recep- Statement of Interest tor compared with D receptor in vivo (Tadori et al., 2011). There are several limitations to this study. First, we per - Y.O. has received grants or speaker’s honoraria from Dainippon formed PET scan after only a single administration of an anti- Sumitomo Pharma, GlaxoSmithKline, Janssen Pharmaceutical, psychotic in 6 healthy subjects. It has been reported that chronic Otsuka, Pfizer, Eli Lilly, Astellas, Yoshitomi, and Meiji within the use of antipsychotics increases D receptors among patients with past 3 years. The remaining authors declare no interest. schizophrenia (Graff-Guerrero et al., 2009). Another study of drug- naïve patients with schizophrenia showed that 2.5 weeks of anti- psychotic treatment doubled BP of D receptors (Mizrahi et al., ND 3 References 2011). These studies indicated that the density of D receptors in Baba S, Enomoto T, Horisawa T, Hashimoto T, Ono M (2015) patients treated with antipsychotics might be different from that Blonanserin extensively occupies rat dopamine D recep- in healthy controls. Thus, to evaluate the precise relationship tors at antipsychotic dose range. J Pharmacol Sci 127: between drug concentration and both D and D receptor occupan- 2 3 326–331. cies, further study with larger sample size, including patients, will Bhathena A, Wang Y, Kraft JB, Idler KB, Abel SJ, Holley-Shanks RR, be needed. Second, 1 of our 6 subjects provided only 70-min data Robieson WZ, Spear B, Reden L, Katz DA (2013). Association of from the PET scan. It was considered that this might affect the dopamine-related genetic loci to dopamine D receptor antag- evaluation of BP . However, the relationship between occupancy ND onist ABT-925 clinical response. 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J Cereb Blood Flow Nakamura H, Kumita S, Okubo Y (2013) Striatal and extrastri- Metab 27:1533–1539. atal dopamine D receptor occupancy by a novel antipsychotic, 11 11 Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000) blonanserin: a PET study with [C]raclopride and [ C]FLB 457 Relationship between dopamine D(2) occupancy, clinical in schizophrenia. J Clin Psychopharmacol 33:162–169. response, and side effects: a double-blind PET study of first- Tenjin T, Miyamoto S, Miyake N, Ogino S, Kitajima R, Ojima K, Arai episode schizophrenia. Am J Psychiatry 157:514–520. J, Teramoto H, Tsukahara S, Ito Y, Tadokoro M, Anai K, Funamoto Kuroki T, Meltzer HY, Ichikawa J (1999) Effects of antipsychotic Y, Kaneda Y, Sumiyoshi T, Yamaguchi N (2012) Effect of blonan- drugs on extracellular dopamine levels in rat medial pre- serin on cognitive function in antipsychotic-naïve first-episode frontal cortex and nucleus accumbens. J Pharmacol Exp Ther schizophrenia. Hum Psychopharmacol 27:90–100. 288:774–781. Tziortzi AC, Searle GE, Tzimopoulou S, Salinas C, Beaver JD, McCormick PN, Kapur S, Graff-Guerrero A, Raymond R, Nobrega Jenkinson M, Laruelle M, Rabiner EA, Gunn RN (2011) Imaging JN, Wilson AA (2010) The antipsychotics olanzapine, risperi- dopamine receptors in humans with [11C]-(+)-PHNO: dissec- done, clozapine, and haloperidol are D -selective ex vivo but tion of D signal and anatomy. Neuroimage 54:264–277. 2 3 not in vitro. Neuropsychopharmacology 35:1826–1835. Willeit M, Ginovart N, Kapur S, Houle S, Hussey D, Seeman P, Mizrahi R, Agid O, Borlido C, Suridjan I, Rusjan P, Houle S, Wilson AA (2006) High-affinity states of human brain dopa- Remington G, Wilson AA, Kapur S (2011) Effects of antip- mine D receptors imaged by the agonist [11C]-(+)-PHNO. 2/3 sychotics on D receptors: a clinical PET study in first Biol Psychiatry 59:389–394. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/522/4807374 by Ed 'DeepDyve' Gillespie user on 21 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Neuropsychopharmacology Oxford University Press

Comparison of Dopamine D3 and D2 Receptor Occupancies by a Single Dose of Blonanserin in Healthy Subjects: A Positron Emission Tomography Study With [11C]-(+)-PHNO

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Abstract

Background: Blockade of D receptor, a member of the dopamine D-like receptor family, has been suggested as a possible 3 2 medication for schizophrenia. Blonanserin has high affinity in vitro for D as well as D receptors. We investigated whether 3 2 a single dose of 12  mg blonanserin, which was within the daily clinical dose range (i.e., 8–24  mg) for the treatment of schizophrenia, occupies D as well as D receptors in healthy subjects. 3 2 Methods: Six healthy males (mean 35.7 ± 7.6 years) received 2 positron emission tomography scans, the first prior to taking blonanserin, and the second 2 hours after the administration of a single dose of 12  mg blonanserin. Dopamine receptor occupancies by blonanserin were evaluated by [C]-(+)-PHNO. Results: Occupancy of each region by 12 mg blonanserin was: caudate (range 64.3%–81.5%; mean ± SD , 74.3 ± 5.6%), putamen (range 60.4%–84.3%; mean± SD, 73.3% ± 8.2%), ventral striatum (range 40.1%–88.2%; mean ± SD , 60.8% ± 17.1%), globus pallidus (range 65.8%–87.6%; mean± SD, 75.7% ± 8.6%), and substantia nigra (range 56.0%–88.7%; mean ± SD, 72.4% ± 11.0%). Correlation analysis between plasma concentration of blonanserin and receptor occupancy in D -rich (caudate and putamen) and D -rich 2 3 (globus pallidus and substantia nigra) regions showed that EC for D -rich region was 0.39 ng/mL (r = 0.43) and EC for D -rich 50 2 50 3 region was 0.40 ng/mL (r= 0.79). Conclusions: A single dose of 12 mg blonanserin occupied D receptor to the same degree as D receptor in vivo. Our results 3 2 were consistent with previous studies that reported that some of the pharmacological effect of blonanserin is mediated via D receptor antagonism. Keywords: D receptor, D receptor, blonanserin, positron emission tomography 2 3 Received: May 10, 2017; Revised: December 14, 2017; Accepted: January 10, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 522 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/522/4807374 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Tateno et al. | 523 Significance Statement The focus of this study was on the occupancies of blonanserin for both dopamine D and D receptors in vivo. This study found 2 3 that 12 mg blonanserin occupied D -rich region (i.e., 75.7% in globus pallidus and 72.4% in substantia nigra) as much as -ric D h 3 2 region (i.e., 74.3% in caudate and 73.3% in putamen) in healthy volunteers. Correlation analysis between the plasma concentra- tion of blonanserin and receptor occupancy showed that the EC values of D -rich regions and D-rich regions are very similar 50 2 3 (0.39  ng/mL, r= 0.43 and 0.40  ng/mL, r= 0.79). Our results indicated the possibility that some of the pharmacological effect of blonanserin is mediated via D receptor antagonism. Introduction The mechanism of the antipsychotic effect of neuroleptics 9–10) similarly to a D-rich region (i.e., striatum) in rat brain, mainly focuses on the antagonism of D receptor (Seeman, 2002). while risperidone, olanzapine, and aripiprazole did not (Baba D receptor antagonism can also induce some adverse effects et al., 2008). Blonanserin demonstrated efficacy against cogni- (e.g., Parkinsonism, hyperprolactinemia), and therefore many tive impairment induced by phencyclidine by inhibiting both researchers have been studying the effects of antipsychotics on dopamine D and serotonin 5-HT receptors in rat (Hida et al., 3 2A the dopaminergic system and other monoaminergic systems, 2015). Thus, blonanserin has been thought to have D antag- and also the association between pharmacological treatment onism identical to D and clinical efficacy by D receptors. 2 3 and the change of monoaminergic systems in vivo. However, there has been no study of the evaluation of D occu- Dopamine D receptor, a member of the dopamine D-like pancy by blonanserin. 3 2 receptor family, localizes in the limbic area and coexists with D In this study, we investigated whether a clinical dose of blo- receptors in the substantia nigra as well as in many other areas nanserin occupies D receptors as well as D receptors in healthy 3 2 in human brain. D receptor has similarities to other members of subjects. the D -like receptor family, but D receptor has very high affinity 2 3 for dopamine and modulates dopamine release as an autore- Methods ceptor (Gross and Drescher, 2012). Some previous studies have reported that selective D receptor antagonists might increase Subjects the extracellular dopamine concentrations in the medial pre- Six healthy male volunteers (range 27–46  years; mean ± SD , frontal cortex (Gross and Drescher, 2012) and are also able to 35.7 ± 7.6) were enrolled. None had a history of present or past increase acetylcholine (Kuroki et  al., 1999). These pharmaco- psychiatric, neurological, or somatic disorders, or alcohol or logical studies and studies of rodent D receptors have suggested substance-related problems. After thorough explanation of the that blockade of D receptor might represent a new treatment study, written informed consent was obtained from all partici- mechanism for schizophrenia (Gross et al., 2013). pants. This study was approved by the review board of Nippon Many atypical antipsychotics and some typical antipsychot- Medical School Hospital, Tokyo, Japan. ics have high affinities for both D and D receptors (Girgis et al., 2 3 2011). Recent technological progress has allowed us to visualize 11 Study Design the distribution of D receptors in vivo. [ C]-(+)-PHNO is a D /D 3 3 2 agonist radioligand for positron emission tomography (PET) with This study was designed as a single administration, open- preferential in vivo selectivity for dopamine D over D receptor 3 2 label protocol. Each subject underwent 2 PET scans, the first (Willeit et al., 2006Gino ; vart et al., 2007). Almost all of the sig- prior to taking blonanserin, and the second 2 hours after being nal of [ C]-(+)-PHNO in both caudate and putamen represented administered of 12  mg blonanserin, which targeted the time- D receptor sites, while up to 100% of the signal in substantia to-maximum blood concentration of blonanserin (Saruwatari nigra, 67% in globus pallidus, and 26% in ventral striatum repre- et al., 2010). sented D receptor sites (Searle et al., 2010). An in vitro affinity study suggested that antipsychotics would occupy D receptors PET Procedures as much as D receptors, although antipsychotics reportedly occupied D receptors moderately less than D receptors (Girgis PET scans were carried out with Eminence SET-3000GCT-X 3 2 et  al., 2011), and a PET study with [C]-(+)-PHNO reported that (Shimadzu Corp) to measure regional brain radioactivity. This antipsychotics (i.e., clozapine, risperidone, olanzapine) did not scanner provides 99 sections with an axial field of view of decrease or even increased the in vivo nondisplaceable binding 26.0 cm. Spatial resolution was 3.45 mm in-plane and 3.72 mm potential (BP ) of D receptors in human brain (Graff-Guerrero axially full-width at half-maximum. A head fixation device was ND 3 et al., 2009). Another study also reported that chronically admin- used during the scans. A 15-min transmission scan was done to istered antipsychotics (i.e., clozapine, olanzapine, and haloperi- 137 correct for attenuation using a Cs source. Dynamic PET scan dol) showed lower selectivity for D compared with D receptors 3 2 was performed for 90 min (1 min× 15, 5 min × 15) after i.v. bolus ex vivo than in vitro in rat brain (McCormick et al., 2010). 11 injection of [ C]-(+)-PHNO. Injected radioactivity was 196.4 to Blonanserin is an atypical antipsychotic, but unlike other 385.0 MBq (348.8 ± 64.2 (mean ± SD MBq) for drug-free condition; atypical antipsychotics, the binding affinity for D receptors 339.8 ± 70.2 MBq for blonanserin condition). The injected mass of (Ki = 0.284 nM) is slightly higher than that for 5-HT receptors 2A [ C]-(+)-PHNO was 1.9  – 2.5 μg (2.2 ± 0.3 μg for drug-free condi- (Ki = 0.64  nM) in vitro (Murasaki et  al., 2008). Blonanserin has tion; 2.4 ± 0.1 μg for blonanserin condition). Specific radioactiv- high in vitro affinity for dopamine D receptor (Ki = 0.277  nM), 3 ity was 41.7  – 95.4 GBq/µmol (77.7 ± 7.5 GBq/µmol for drug-free similar to that for D receptor (Ki= 0.284 nM) (Baba et al., 2008). condition; 77.9 ± 7.5 GBq/µmol for blonanserin condition) at the Blonanserin occupied a D-rich region (i.e., cerebellum lobe 3 time of injection. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/522/4807374 by Ed 'DeepDyve' Gillespie user on 21 June 2018 524 | International Journal of Neuropsychopharmacology, 2018 receptor occupancy between in vitro and in vivo studies has MRI Procedures been reported (Graff-Guerrero et  al., 2010McCormic ; k et  al., Magnetic resonance (MR) images of the brain were acquired 2010), correlations between plasma concentration and recep- with 1.5T MR imaging, Intera 1.5T Achieve Nova (Philips Medical tor occupancy were examined. Systems) as proton density image (echo time = 17 msec; repe- tition time= 6000 msec; field of view = 22  cm, 2-dimensional, Results 256 × 256; slice thickness = 2  mm; number of excitations = 2). These images were used for analysis of the PET scans. Five subjects each completed two 90-min PET scans with [ C]-(+)-PHNO. One subject provided partial data: the first PET scan (drug-free condition) was stopped at 70  min because of Measurement of Plasma Concentration of the subject’s anxiety. We then included both conditions of 0 to Blonanserin 70 min PET data of this subject. Venous blood samples were taken just before second PET scans Figure  1 shows BP of each ROI in each condition. Average ND (2 hours after taking 12 mg blonanserin), collected in tubes con- BP in drug-free condition was as follows: caudate (BP range ND ND taining EDTA-2Na, and centrifuged at 3000 rpm for 10 min at 4ºC. 1.04–1.68; mean ± SD, 1.53 ± 0.24), putamen (BP range 1.28–2.06; ND Separated plasma samples were stored at -80ºC until analysis. 1.82 ± 0.29), ventral striatum (BP range 1.59–2.85; 2.40± 0.43), ND Plasma concentration was measured by validated method using globus pallidus (BP range 1.56–2.68; 2.16± 0.40), and substantia ND high-performance liquid chromatography-tandem mass spec- nigra (BP range 0.96–1.42; 1.06± 0.17). Average BP in blonan- ND ND trometry with a target lower quantification limit of 0.001 ng/mL serin condition was as follows: caudate (BP range 0.27–0.60; ND (Sekisui Medical Co., Ltd.). 0.40 ± 0.12), putamen (BP range 0.20–0.77; 0.50± 0.19), ventral ND striatum (BP range 0.19–1.70; 0.99± 0.52), globus pallidus (BP ND ND range 0.19–0.91; 0.54± 0.24), and substantia nigra (BP range ND Data Analysis 0.11–0.47; 0.30 ± 0.13). The average level of receptor occupancy by a single dose of blonanserin 12  mg was as follows: cau- MR images were co-registered to summated PET images date (range 64.3–81.5; 74.3± 5.6%), putamen (range 60.4–84.3; with the mutual information algorithm using PMOD (v - er 73.3 ± 8.2%), ventral striatum (range 40.1–88.2; 60.8 ± 17.1%), glo- sion 3.4; PMOD Technologies Ltd). Regions of interest (ROIs) bus pallidus (range 65.8–87.6; 75.7 ± 8.6%), and substantia nigra were defined for the caudate, putamen, ventral striatum, glo- (range 56.0–88.7; 72.4± 11.0%) (Table 1). bus pallidus, and substantia nigra, and were drawn manu- The average drug concentration of blonanserin was 1.49 ± 0.88 ally in accordance with Tziortzi’s study (Tziortzi et al., 2011). (mean ± SD) ng/mL (range 0.58–2.90). Correlations between We defined the caudate and putamen as D-rich regions and plasma concentration of blonanserin and receptor occupancy in the substantia nigra and globus pallidus as D -rich regions, D -rich and D -rich ROI are shown in Figure 2. EC was 0.39 ng/ according to Searle’s study (Searle et  al., 2010). ROIs were 2 3 50 mL (df = 11, r = 0.43) for D-rich region and 0.40  ng/mL (df= 11, drawn manually on overlaid summated PET and co-r egistered r = 0.79) for D -rich region. MR images of each subject. By matching the targeted frame to the average of the first 10 frames (i.e., 0–10 minutes), motion corrections were conducted in 3 scans of 2 subjects because Discussion of head movements. In this study, we examined the receptor occupancies in both D - Quantitative estimate of binding of [C]-(+)-PHNO was per- rich and D -rich regions by a single dose of 12 mg blonanserin formed using a simplified reference tissue model (Lammertsma using [ C]-(+)-PHNO PET. A  single dose of 12  mg blonanserin and Hume, 1996), with the cerebellar cortex as reference region. occupied dopamine receptors in D-rich regions (i.e., substantia This model has been validated to reliably estimate BP , which ND nigra, globus pallidus) as much as in D -rich regions (i.e., cau- compares the concentration of radioligand in the receptor- date, putamen). Receptor occupancy in the striatum by 12  mg rich region with the receptor-free region (Innis et al., 2007), for blonanserin (74.3% for caudate and 73.3% for putamen) was [ C]-(+)-PHNO (Ginovart et al., 2007). almost the same as by [ C]raclopride (68.5% for the striatum as Receptor occupancy by drugs was calculated by the following calculated based on our previous data; Tateno et al., 2013). Thus, equation: a single dose of 12 mg blonanserin, within the clinical daily dose Occupancy () %/ =- BP BP BP ´ 100, () NDbase NDdrug NDbase range for the treatment of schizophrenia, occupied D receptors to approximately the same extent as D receptors. Thus, this is where occupancy is the receptor occupancy, BP is BP NDbase ND the first study to show that this dopamine antagonist occupied under drug-free condition, and BP is BP under blonan- NDdrug ND both D and D receptors at about the same levels. 2 3 serin condition. Since dopaminergic hypofunction in the prefrontal cortex has We used a 1-site binding model, the same as a previous study been implicated in the pathogenesis of negative symptoms (Davis (Graff-Guerrero et  al., 2010). The relationship between plasma et al., 1991) and cognitive dysfunctions of schizophrenia (Sawaguchi, concentration and receptor occupancy was shown by the follow- 2000), D receptor antagonism might improve the negative symp- ing equation: toms and cognitive deficits of schizophrenia. Animal studies have Occupancy () %/ =´ E C E () C+C ´ 100, reported that blonanserin showed cognitive efficacy via D recep- max50 tor antagonism and that it had a beneficial effect on prefrontal dopamine transmission (Gross et  al., 2013Nakajima et  ; al., 2013; where C is the plasma concentration of drug, E is the max maximum occupancy, and EC is the plasma concentra- Hida et  al., 2015). Other clinical studies showed that blonanserin induced improvements in verbal fluency and executive function tion required to achieve 50% occupancy (Takano et al., 2006; Graff-Guerrero et  al., 2010). E was fixed at 1 and EC > 0, (Tenjin et  al., 2012; Hori et  al., 2014), which might be related to max 50 the effect of this antipsychotic on dopamine transmission pre- the same as in previous occupancy studies (Takano et  al., 2006; Graff-Guerrero et  al., 2010). Since discrepancy of D frontal cortex function. It has also been reported that functional Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/522/4807374 by Ed 'DeepDyve' Gillespie user on 21 June 2018 Tateno et al. | 525 Figure 1. Binding potential (BP ) of [ C]-(+)-PHNO for every region of interest before and after taking 12 mg blonanserin. Filled circles represent the subject with 70-min ND PET scans. Table  1. Average Binding Potential and Occupancy of Dopamine that a single dose of 12  mg blonanserin antagonizes D receptor Receptors in Each Region as much as D receptor, as has been indicated by previous studies (Baba et al., 2015), and therefore further study regarding what per - Region of Interest Drug-free Blonanserin Occupancy (%) centage of D occupancy by antipsychotics might improve cogni- tion could be beneficial for treatment strategies of schizophrenia. Caudate 1.53 ± 0.24 0.40 ± 0.12 74.3 ± 5.6 Putamen 1.82 ± 0.29 0.50 ± 0.20 73.3 ± 8.2 The mechanism underlying the discrepancies between in Globus pallidus 2.16 ± 0.40 0.54 ± 0.24 75.7 ± 8.6 vitro and in vivo bindings of several antipsychotics to dopamine Ventral striatum 2.40 ± 0.43 0.99 ± 0.52 60.8 ± 17.1 D receptors (Graff-Guerrero et al., 2010 McCormic ; k et al., 2010) is Substantia nigra 1.06 ± 0.17 0.30 ± 0.13 72.4 ± 11.0 still unclear. However, several explanations have been proposed. Girgis presented the upregulation scenario (Girgis et  al., 2011). The study in baboons demonstrated binding of both D and D 2 3 connectivity between the prefrontal cortex and salience/executive receptors by an acute dose of haloperidol (haloperidol: 70% of control networks negatively associated with midbrain D receptor putamen and 61% of globus pallidus, clozapine: 43% of putamen availability (Cole et  al., 2011). Many PET studies have suggested and 21% of globus pallidus). Girgis further suggested that upreg- that around 70% to 80% D receptor occupancy in the striatum is ulation of D receptor induced by chronic use of antipsychot- required for an antipsychotic effect with a lower risk of extrap - yr ics might affect the discrepancy between the results of in vitro amidal adverse effects (Farde et  al., 1992Nor ; dström et  al., 1993; affinity study and in vivo PET study (Girgis et al., 2011). Our study Kapur et al., 2000). Previous studies showed that 150 mg of ABT-925, participants were healthy volunteers with a single administra- a selective D receptor antagonist, possibly improves positive and tion, and our result was consistent with this scenario. Another negative symptoms of schizophrenia, and that it occupied about explanation could be the influence of endogenous dopamine. 30% of D receptors in substantia nigra and globus pallidus (Graff- Schotte reported that the D /D potency ratios of antipsychotics 2 3 Guerrero et al., 2010Bhathena et  ; al., 2013). A recent study showed (i.e., clozapine, olanzapine, risperidone, haloperidol) in vivo were that a clinical dose of cariprazine, a D -preferring dual D/D recep- 2 to 10 times higher than those of in vitro competitive binding 3 3 2 tor partial agonist for the treatment of schizophrenia, occupied at experiments (Schotte et al., 1996), and they suggested that this least 76% of D receptors, along with 45% of D receptors (Girgis effect was due to the in vivo inhibitory influence of endogenous 3 2 et  al., 2016). However, the adequate degree of D receptor occu- dopamine. It has been suggested that antipsychotics inhibit D 3 2 pancy for an antipsychotic effect or improvement of motivation and D receptors in a dose-dependent manner, but the relation- and/or cognition has been unclear. Our result provided evidence ship between drug concentration and inhibitory effect differed Downloaded from https://academic.oup.com/ijnp/article-abstract/21/6/522/4807374 by Ed 'DeepDyve' Gillespie user on 21 June 2018 526 | International Journal of Neuropsychopharmacology, 2018 Figure 2. Correlation between receptor occupancy in D -rich (caudate and putamen) and D -rich (globus pallidus and substantia nigra) regions with [ C]-(+)-PHNO and 2 3 plasma concentration of 12 mg blonanserin. Filled circles represent the subject with 70-min PET scans. according to the respective antipsychotics. Tadori reported that Megumi Hongo, and Minoru Sakurai for their assistance in most antipsychotics at clinical dose sufficiently antagonize D performing the PET experiments and MRI scanning, and receptor signals but not D receptor signals, while blonanserin, Michiyo Tamura for her help as clinical research coordin- haloperidol, and fluphenazine inhibit D receptor at a similar ator (Clinical Imaging Center for Healthcare, Nippon Medical level to D receptor (Tadori et  al., 2011). Their study suggested School, Tokyo, Japan). that a clinical dose of antipsychotics, except for blonanserin, haloperidol, and fluphenazine, preferentially inhibits D recep- Statement of Interest tor compared with D receptor in vivo (Tadori et al., 2011). There are several limitations to this study. First, we per - Y.O. has received grants or speaker’s honoraria from Dainippon formed PET scan after only a single administration of an anti- Sumitomo Pharma, GlaxoSmithKline, Janssen Pharmaceutical, psychotic in 6 healthy subjects. It has been reported that chronic Otsuka, Pfizer, Eli Lilly, Astellas, Yoshitomi, and Meiji within the use of antipsychotics increases D receptors among patients with past 3 years. The remaining authors declare no interest. schizophrenia (Graff-Guerrero et al., 2009). Another study of drug- naïve patients with schizophrenia showed that 2.5 weeks of anti- psychotic treatment doubled BP of D receptors (Mizrahi et al., ND 3 References 2011). These studies indicated that the density of D receptors in Baba S, Enomoto T, Horisawa T, Hashimoto T, Ono M (2015) patients treated with antipsychotics might be different from that Blonanserin extensively occupies rat dopamine D recep- in healthy controls. Thus, to evaluate the precise relationship tors at antipsychotic dose range. J Pharmacol Sci 127: between drug concentration and both D and D receptor occupan- 2 3 326–331. cies, further study with larger sample size, including patients, will Bhathena A, Wang Y, Kraft JB, Idler KB, Abel SJ, Holley-Shanks RR, be needed. Second, 1 of our 6 subjects provided only 70-min data Robieson WZ, Spear B, Reden L, Katz DA (2013). Association of from the PET scan. It was considered that this might affect the dopamine-related genetic loci to dopamine D receptor antag- evaluation of BP . However, the relationship between occupancy ND onist ABT-925 clinical response. Transl Psychiatry 3:e245. of receptors and drug concentration was almost unchanged when Cole DM, Beckmann CF, Searle GE, Plisson C, Tziortzi AC, Nichols excluding this subject (in caudate: r = 1.00, EC = 0.38; in putamen: TE, Gunn RN, Matthews PM, Rabiner EA, Beaver JD (2012) r = 0.77, EC = 0.42; in ventral striatum: r = 0.62, EC = 0.82; in globus 50 50 Orbitofrontal connectivity with resting-state networks is pallidus: r = 0.79, EC = 0.38; in substantia nigra: r = 0.85, EC = 0.46). 50 50 associated with midbrain dopamine D receptor availability. In conclusion, our study using [C]-(+)-PHNO demonstrated Cereb Cortex 22:2784–2793. that a single dose of 12 mg blonanserin could occupy D recep- Davis KL, Kahn RS, Ko G, Davidson M (1991) Dopamine in schizo- tors to the same degree as D receptors in vivo. Our results indi- phrenia: a review and reconceptualization. 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International Journal of NeuropsychopharmacologyOxford University Press

Published: Jan 13, 2018

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