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

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

N1 - Copyright © 2010 Elsevier Inc. All rights reserved.

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 -