Systemic catechol-O-methyl transferase inhibition enables the D1 agonist radiotracer R-[11C]SKF 82957

Mikael Palner; Patrick McCormick; Jun Parkes; Gitte M Knudsen; Alan A Wilson

doi:10.1016/j.nucmedbio.2010.04.193

Systemic catechol-O-methyl transferase inhibition enables the D1 agonist radiotracer R-[11C]SKF 82957

Mikael Palner, Patrick McCormick, Jun Parkes, Gitte M Knudsen, Alan A Wilson

Institut for Klinisk Medicin

12 Citationer (Scopus)

Abstract

Introduction: R-[¹¹C]-SKF 82957 is a high-affinity and potent dopamine D₁ receptor agonist radioligand, which gives rise to a brain-penetrant lipophilic metabolite. In this study, we demonstrate that systemic administration of catechol-O-methyl transferase (COMT) inhibitors blocks this metabolic pathway, facilitating the use of R-[¹¹C]-SKF 82957 to image the high-affinity state of the dopamine D₁ receptor with PET. Methods: R-[¹¹C]SKF 82957 was administered to untreated and COMT inhibitor-treated conscious rats, and the radioactive metabolites present in the brain and plasma were quantified by HPLC. Under optimal conditions, cerebral uptake and dopamine D₁ binding of R-[¹¹C]SKF 82957 were measured ex vivo. In addition, pharmacological challenges with the receptor antagonist SCH 23390, amphetamine, the dopamine reuptake inhibitor RTI-32 and the dopamine hydroxylase inhibitor α-methyl-p-tyrosine were performed to study the specificity and sensitivity of R-[¹¹C]-SKF 82957 dopamine D₁ binding in COMT-inhibited animals. Results: Treatment with the COMT inhibitor tolcapone was associated with a dose-dependent (EC₉₀ 5.3±4.3 mg/kg) reduction in the lipophilic metabolite. Tolcapone treatment (20 mg/kg) also resulted in a significant increase in the striatum/cerebellum ratio of R-[¹¹C]SKF 82957, from 15 (controls) to 24. Treatment with the dopamine D₁ antagonist SCH 23390 reduced the striatal binding to the levels of the cerebellum, demonstrating a high specificity and selectivity of R-[¹¹C]SKF 82957 binding. Conclusions: Pre-treatment with the COMT inhibitor tolcapone inhibits formation of an interfering metabolite of R-[¹¹C]SKF 82957. Under such conditions, R-[¹¹C]SKF 82957 demonstrates high potential as the first agonist radiotracer for imaging the dopamine D₁ receptor by PET.

Originalsprog	Engelsk
Tidsskrift	Nuclear Medicine and Biology
Vol/bind	37
Udgave nummer	7
Sider (fra-til)	837-43
Antal sider	7
ISSN	0969-8051
DOI	https://doi.org/10.1016/j.nucmedbio.2010.04.193
Status	Udgivet - 1 okt. 2010

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10.1016/j.nucmedbio.2010.04.193

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@article{12f5ca4df136454cac1203891d0e0048,

title = "Systemic catechol-O-methyl transferase inhibition enables the D1 agonist radiotracer R-[11C]SKF 82957",

abstract = "Introduction: R-[11C]-SKF 82957 is a high-affinity and potent dopamine D1 receptor agonist radioligand, which gives rise to a brain-penetrant lipophilic metabolite. In this study, we demonstrate that systemic administration of catechol-O-methyl transferase (COMT) inhibitors blocks this metabolic pathway, facilitating the use of R-[11C]-SKF 82957 to image the high-affinity state of the dopamine D1 receptor with PET. Methods: R-[11C]SKF 82957 was administered to untreated and COMT inhibitor-treated conscious rats, and the radioactive metabolites present in the brain and plasma were quantified by HPLC. Under optimal conditions, cerebral uptake and dopamine D1 binding of R-[11C]SKF 82957 were measured ex vivo. In addition, pharmacological challenges with the receptor antagonist SCH 23390, amphetamine, the dopamine reuptake inhibitor RTI-32 and the dopamine hydroxylase inhibitor α-methyl-p-tyrosine were performed to study the specificity and sensitivity of R-[11C]-SKF 82957 dopamine D1 binding in COMT-inhibited animals. Results: Treatment with the COMT inhibitor tolcapone was associated with a dose-dependent (EC90 5.3±4.3 mg/kg) reduction in the lipophilic metabolite. Tolcapone treatment (20 mg/kg) also resulted in a significant increase in the striatum/cerebellum ratio of R-[11C]SKF 82957, from 15 (controls) to 24. Treatment with the dopamine D1 antagonist SCH 23390 reduced the striatal binding to the levels of the cerebellum, demonstrating a high specificity and selectivity of R-[11C]SKF 82957 binding. Conclusions: Pre-treatment with the COMT inhibitor tolcapone inhibits formation of an interfering metabolite of R-[11C]SKF 82957. Under such conditions, R-[11C]SKF 82957 demonstrates high potential as the first agonist radiotracer for imaging the dopamine D1 receptor by PET.",

keywords = "Animals, Benzazepines, Benzophenones, Brain, Carbon Radioisotopes, Catechol O-Methyltransferase, Catechols, Dopamine Agonists, Enzyme Inhibitors, Nitriles, Nitrophenols, Positron-Emission Tomography, Radiopharmaceuticals, Rats, Receptors, Dopamine D1, Tissue Distribution",

author = "Mikael Palner and Patrick McCormick and Jun Parkes and Knudsen, {Gitte M} and Wilson, {Alan A}",

year = "2010",

month = oct,

day = "1",

doi = "10.1016/j.nucmedbio.2010.04.193",

language = "English",

volume = "37",

pages = "837--43",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

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number = "7",

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TY - JOUR

T1 - Systemic catechol-O-methyl transferase inhibition enables the D1 agonist radiotracer R-[11C]SKF 82957

AU - Palner, Mikael

AU - McCormick, Patrick

AU - Parkes, Jun

AU - Knudsen, Gitte M

AU - Wilson, Alan A

PY - 2010/10/1

Y1 - 2010/10/1

N2 - Introduction: R-[11C]-SKF 82957 is a high-affinity and potent dopamine D1 receptor agonist radioligand, which gives rise to a brain-penetrant lipophilic metabolite. In this study, we demonstrate that systemic administration of catechol-O-methyl transferase (COMT) inhibitors blocks this metabolic pathway, facilitating the use of R-[11C]-SKF 82957 to image the high-affinity state of the dopamine D1 receptor with PET. Methods: R-[11C]SKF 82957 was administered to untreated and COMT inhibitor-treated conscious rats, and the radioactive metabolites present in the brain and plasma were quantified by HPLC. Under optimal conditions, cerebral uptake and dopamine D1 binding of R-[11C]SKF 82957 were measured ex vivo. In addition, pharmacological challenges with the receptor antagonist SCH 23390, amphetamine, the dopamine reuptake inhibitor RTI-32 and the dopamine hydroxylase inhibitor α-methyl-p-tyrosine were performed to study the specificity and sensitivity of R-[11C]-SKF 82957 dopamine D1 binding in COMT-inhibited animals. Results: Treatment with the COMT inhibitor tolcapone was associated with a dose-dependent (EC90 5.3±4.3 mg/kg) reduction in the lipophilic metabolite. Tolcapone treatment (20 mg/kg) also resulted in a significant increase in the striatum/cerebellum ratio of R-[11C]SKF 82957, from 15 (controls) to 24. Treatment with the dopamine D1 antagonist SCH 23390 reduced the striatal binding to the levels of the cerebellum, demonstrating a high specificity and selectivity of R-[11C]SKF 82957 binding. Conclusions: Pre-treatment with the COMT inhibitor tolcapone inhibits formation of an interfering metabolite of R-[11C]SKF 82957. Under such conditions, R-[11C]SKF 82957 demonstrates high potential as the first agonist radiotracer for imaging the dopamine D1 receptor by PET.

AB - Introduction: R-[11C]-SKF 82957 is a high-affinity and potent dopamine D1 receptor agonist radioligand, which gives rise to a brain-penetrant lipophilic metabolite. In this study, we demonstrate that systemic administration of catechol-O-methyl transferase (COMT) inhibitors blocks this metabolic pathway, facilitating the use of R-[11C]-SKF 82957 to image the high-affinity state of the dopamine D1 receptor with PET. Methods: R-[11C]SKF 82957 was administered to untreated and COMT inhibitor-treated conscious rats, and the radioactive metabolites present in the brain and plasma were quantified by HPLC. Under optimal conditions, cerebral uptake and dopamine D1 binding of R-[11C]SKF 82957 were measured ex vivo. In addition, pharmacological challenges with the receptor antagonist SCH 23390, amphetamine, the dopamine reuptake inhibitor RTI-32 and the dopamine hydroxylase inhibitor α-methyl-p-tyrosine were performed to study the specificity and sensitivity of R-[11C]-SKF 82957 dopamine D1 binding in COMT-inhibited animals. Results: Treatment with the COMT inhibitor tolcapone was associated with a dose-dependent (EC90 5.3±4.3 mg/kg) reduction in the lipophilic metabolite. Tolcapone treatment (20 mg/kg) also resulted in a significant increase in the striatum/cerebellum ratio of R-[11C]SKF 82957, from 15 (controls) to 24. Treatment with the dopamine D1 antagonist SCH 23390 reduced the striatal binding to the levels of the cerebellum, demonstrating a high specificity and selectivity of R-[11C]SKF 82957 binding. Conclusions: Pre-treatment with the COMT inhibitor tolcapone inhibits formation of an interfering metabolite of R-[11C]SKF 82957. Under such conditions, R-[11C]SKF 82957 demonstrates high potential as the first agonist radiotracer for imaging the dopamine D1 receptor by PET.

KW - Animals

KW - Benzazepines

KW - Benzophenones

KW - Brain

KW - Carbon Radioisotopes

KW - Catechol O-Methyltransferase

KW - Catechols

KW - Dopamine Agonists

KW - Enzyme Inhibitors

KW - Nitriles

KW - Nitrophenols

KW - Positron-Emission Tomography

KW - Radiopharmaceuticals

KW - Rats

KW - Receptors, Dopamine D1

KW - Tissue Distribution

U2 - 10.1016/j.nucmedbio.2010.04.193

DO - 10.1016/j.nucmedbio.2010.04.193

M3 - Journal article

C2 - 20870159

SN - 0969-8051

VL - 37

SP - 837

EP - 843

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

IS - 7

ER -

Systemic catechol-O-methyl transferase inhibition enables the D1 agonist radiotracer R-[11C]SKF 82957

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