Striatal and extrastriatal dopamine D 2 receptor occupancy by the partial agonist antipsychotic drug aripiprazole in the human brain: A positron emission tomography study with [ 11C]raclopride and [ 11C]FLB457

Keisuke Takahata; Hiroshi Ito; Harumasa Takano; Ryosuke Arakawa; Hironobu Fujiwara; Yasuyuki Kimura; Fumitoshi Kodaka; Takeshi Sasaki; Tsuyoshi Nogami; Masayuki Suzuki; Tomohisa Nagashima; Hitoshi Shimada; Motoichiro Kato; Masaru Mimura; Tetsuya Suhara

doi:10.1007/s00213-011-2633-5

Striatal and extrastriatal dopamine D ₂ receptor occupancy by the partial agonist antipsychotic drug aripiprazole in the human brain: A positron emission tomography study with [ ¹¹C]raclopride and [ ¹¹C]FLB457

Keisuke Takahata, Hiroshi Ito, Harumasa Takano, Ryosuke Arakawa, Hironobu Fujiwara, Yasuyuki Kimura, Fumitoshi Kodaka, Takeshi Sasaki, Tsuyoshi Nogami, Masayuki Suzuki, Tomohisa Nagashima, Hitoshi Shimada, Motoichiro Kato, Masaru Mimura, Tetsuya Suhara

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

Rationale: Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D ₂ receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D ₂ receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D ₂ receptors have reported inconsistent results regarding regional differences of dopamine D ₂ receptor occupancy by aripiprazole. Objective: To test the hypothesis of preferential binding to extrastriatal dopamine D ₂ receptors by aripiprazole, we investigated its regional dopamine D ₂ receptor occupancies in healthy young subjects. Materials and methods: Using PET and two radioligands with different affinities for dopamine D ₂ receptors, [ ¹¹C] raclopride and [ ¹¹C]FLB457, striatal and extrastriatal dopamine D ₂ receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy subjects. Results: Our data showed that dopamine D ₂ receptor occupancies in the striatum measured with [ ¹¹C]raclopride were 70.1% and 74.1%, with the corresponding values for the extrastriatal regions measured with [ ¹¹C]FLB457 ranging from 46.6% to 58.4%. Conclusions: In the present study, preferential extrastriatal dopamine D ₂ receptor occupancy by aripiprazole was not observed. Our data suggest partial agonism at dopamine D ₂ receptors is the most likely explanation for the minimal risk of extrapyramidal side effects in the treatment by aripiprazole.

Original language	English
Pages (from-to)	165-172
Number of pages	8
Journal	Psychopharmacology
Volume	222
Issue number	1
DOIs	https://doi.org/10.1007/s00213-011-2633-5
Publication status	Published - 2012 Jul
Externally published	Yes

Keywords

Antipsychotics
Aripiprazole
Dopamine D receptor
Occupancy
Partial agonist

ASJC Scopus subject areas

Pharmacology

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Takahata, K., Ito, H., Takano, H., Arakawa, R., Fujiwara, H., Kimura, Y., Kodaka, F., Sasaki, T., Nogami, T., Suzuki, M., Nagashima, T., Shimada, H., Kato, M., Mimura, M., & Suhara, T. (2012). Striatal and extrastriatal dopamine D ₂ receptor occupancy by the partial agonist antipsychotic drug aripiprazole in the human brain: A positron emission tomography study with [ ¹¹C]raclopride and [ ¹¹C]FLB457. Psychopharmacology, 222(1), 165-172. https://doi.org/10.1007/s00213-011-2633-5

Striatal and extrastriatal dopamine D ₂ receptor occupancy by the partial agonist antipsychotic drug aripiprazole in the human brain: A positron emission tomography study with [ ¹¹C]raclopride and [ ¹¹C]FLB457. / Takahata, Keisuke; Ito, Hiroshi; Takano, Harumasa et al.
In: Psychopharmacology, Vol. 222, No. 1, 07.2012, p. 165-172.

Research output: Contribution to journal › Article › peer-review

Takahata, K, Ito, H, Takano, H, Arakawa, R, Fujiwara, H, Kimura, Y, Kodaka, F, Sasaki, T, Nogami, T, Suzuki, M, Nagashima, T, Shimada, H, Kato, M, Mimura, M & Suhara, T 2012, 'Striatal and extrastriatal dopamine D ₂ receptor occupancy by the partial agonist antipsychotic drug aripiprazole in the human brain: A positron emission tomography study with [ ¹¹C]raclopride and [ ¹¹C]FLB457', Psychopharmacology, vol. 222, no. 1, pp. 165-172. https://doi.org/10.1007/s00213-011-2633-5

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title = "Striatal and extrastriatal dopamine D 2 receptor occupancy by the partial agonist antipsychotic drug aripiprazole in the human brain: A positron emission tomography study with [ 11C]raclopride and [ 11C]FLB457",

abstract = "Rationale: Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D 2 receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D 2 receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D 2 receptors have reported inconsistent results regarding regional differences of dopamine D 2 receptor occupancy by aripiprazole. Objective: To test the hypothesis of preferential binding to extrastriatal dopamine D 2 receptors by aripiprazole, we investigated its regional dopamine D 2 receptor occupancies in healthy young subjects. Materials and methods: Using PET and two radioligands with different affinities for dopamine D 2 receptors, [ 11C] raclopride and [ 11C]FLB457, striatal and extrastriatal dopamine D 2 receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy subjects. Results: Our data showed that dopamine D 2 receptor occupancies in the striatum measured with [ 11C]raclopride were 70.1% and 74.1%, with the corresponding values for the extrastriatal regions measured with [ 11C]FLB457 ranging from 46.6% to 58.4%. Conclusions: In the present study, preferential extrastriatal dopamine D 2 receptor occupancy by aripiprazole was not observed. Our data suggest partial agonism at dopamine D 2 receptors is the most likely explanation for the minimal risk of extrapyramidal side effects in the treatment by aripiprazole.",

keywords = "Antipsychotics, Aripiprazole, Dopamine D receptor, Occupancy, Partial agonist",

author = "Keisuke Takahata and Hiroshi Ito and Harumasa Takano and Ryosuke Arakawa and Hironobu Fujiwara and Yasuyuki Kimura and Fumitoshi Kodaka and Takeshi Sasaki and Tsuyoshi Nogami and Masayuki Suzuki and Tomohisa Nagashima and Hitoshi Shimada and Motoichiro Kato and Masaru Mimura and Tetsuya Suhara",

note = "Funding Information: Acknowledgments This study was supported in part by a Grant-in-Aid for the Molecular Imaging Program from the Ministry of Education, Culture, Sports, Science and Technology, Japanese Government. We thank Mr. Katsuyuki Tanimoto and Mr. Takahiro Shiraishi for their assistance in performing the PET experiments, Ms. Kazuko Suzuki and Ms. Izumi Izumida for their help as clinical research coordinators, Dr. Takaaki Mori, Dr. Hajime Fukuda and Ms. Yoko Eguchi for their clinical support, and Ms. Mika Omatsu and Ms. Rie Inagaki for their help in performing MRI scanning.",

year = "2012",

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doi = "10.1007/s00213-011-2633-5",

language = "English",

volume = "222",

pages = "165--172",

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T1 - Striatal and extrastriatal dopamine D 2 receptor occupancy by the partial agonist antipsychotic drug aripiprazole in the human brain

T2 - A positron emission tomography study with [ 11C]raclopride and [ 11C]FLB457

AU - Takahata, Keisuke

AU - Ito, Hiroshi

AU - Takano, Harumasa

AU - Arakawa, Ryosuke

AU - Fujiwara, Hironobu

AU - Kimura, Yasuyuki

AU - Kodaka, Fumitoshi

AU - Sasaki, Takeshi

AU - Nogami, Tsuyoshi

AU - Suzuki, Masayuki

AU - Nagashima, Tomohisa

AU - Shimada, Hitoshi

AU - Kato, Motoichiro

AU - Mimura, Masaru

AU - Suhara, Tetsuya

N1 - Funding Information: Acknowledgments This study was supported in part by a Grant-in-Aid for the Molecular Imaging Program from the Ministry of Education, Culture, Sports, Science and Technology, Japanese Government. We thank Mr. Katsuyuki Tanimoto and Mr. Takahiro Shiraishi for their assistance in performing the PET experiments, Ms. Kazuko Suzuki and Ms. Izumi Izumida for their help as clinical research coordinators, Dr. Takaaki Mori, Dr. Hajime Fukuda and Ms. Yoko Eguchi for their clinical support, and Ms. Mika Omatsu and Ms. Rie Inagaki for their help in performing MRI scanning.

PY - 2012/7

Y1 - 2012/7

N2 - Rationale: Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D 2 receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D 2 receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D 2 receptors have reported inconsistent results regarding regional differences of dopamine D 2 receptor occupancy by aripiprazole. Objective: To test the hypothesis of preferential binding to extrastriatal dopamine D 2 receptors by aripiprazole, we investigated its regional dopamine D 2 receptor occupancies in healthy young subjects. Materials and methods: Using PET and two radioligands with different affinities for dopamine D 2 receptors, [ 11C] raclopride and [ 11C]FLB457, striatal and extrastriatal dopamine D 2 receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy subjects. Results: Our data showed that dopamine D 2 receptor occupancies in the striatum measured with [ 11C]raclopride were 70.1% and 74.1%, with the corresponding values for the extrastriatal regions measured with [ 11C]FLB457 ranging from 46.6% to 58.4%. Conclusions: In the present study, preferential extrastriatal dopamine D 2 receptor occupancy by aripiprazole was not observed. Our data suggest partial agonism at dopamine D 2 receptors is the most likely explanation for the minimal risk of extrapyramidal side effects in the treatment by aripiprazole.

AB - Rationale: Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D 2 receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D 2 receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D 2 receptors have reported inconsistent results regarding regional differences of dopamine D 2 receptor occupancy by aripiprazole. Objective: To test the hypothesis of preferential binding to extrastriatal dopamine D 2 receptors by aripiprazole, we investigated its regional dopamine D 2 receptor occupancies in healthy young subjects. Materials and methods: Using PET and two radioligands with different affinities for dopamine D 2 receptors, [ 11C] raclopride and [ 11C]FLB457, striatal and extrastriatal dopamine D 2 receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy subjects. Results: Our data showed that dopamine D 2 receptor occupancies in the striatum measured with [ 11C]raclopride were 70.1% and 74.1%, with the corresponding values for the extrastriatal regions measured with [ 11C]FLB457 ranging from 46.6% to 58.4%. Conclusions: In the present study, preferential extrastriatal dopamine D 2 receptor occupancy by aripiprazole was not observed. Our data suggest partial agonism at dopamine D 2 receptors is the most likely explanation for the minimal risk of extrapyramidal side effects in the treatment by aripiprazole.

KW - Antipsychotics

KW - Aripiprazole

KW - Dopamine D receptor

KW - Occupancy

KW - Partial agonist

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