RT Journal Article
SR Electronic
T1 Systemic COMT inhibition enables the D1 agonist radiotracer [11C]-(R)-SKF82957
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1185
OP 1185
VO 50
IS supplement 2
A1 Mikael Palner
A1 Patrick McCormick
A1 Jun Parkes
A1 Gitte Knudsen
A1 Alan Wilson
YR 2009
UL http://jnm.snmjournals.org/content/50/supplement_2/1185.abstract
AB 1185 Objectives The catechol D1 agonist, [11C]-(R)-SKF82957, ([11C]-SKF), is metabolised to a labelled, lipophilic, brain penetrating metabolite, limiting its use as a radiotracer for imaging dopamine D1 receptors. We investigated the effect of catechol-O-methyltransferase (COMT) inhibitors on the formation of the interfering metabolite. The objective was to obtain conditions whereby [11C]-SKF could be used to image the high-affinity state of the D1 receptor. Methods Groups of rats were pre-treated with various doses of two COMT inhibitors, entacapone and tolcapone, prior to injection of [11C]-SKF. Radiolabelled metabolites in plasma and brain extracts were quantified by radio-HPLC. To determine specific binding to D1 receptors, rats were also pre-treated with the D1 antagonist, SCH 23390 (2 mg/kg) and activity in striatum and cerebellum counted to determine specific binding ratios (SBR). Results All doses of either COMT inhibitor reduced the metabolism of [11C]-SKF. Concentrations of lipophilic metabolite in brain and plasma were concomitant. Under best conditions (20 mg/kg tolcapone IP) essentially no lipophilic metabolite could be detected in brain or plasma. SBR increased from 14.4±1.6 in the non-COMT treated group to 23.3±3.3 upon best COMT treatment (n=>6). Pretreatment with SCH 23390 reduced the SBR to 0.66±0.2, demonstrating the specificity of binding of [11C]-SKF to D1 receptors. Conclusions Conditions have been determined which enable the use of [11C]SKF as an agonist radiotracer for PET imaging of dopamine D1 receptors. Inhibiition of radiolabeled lipophilic metabolites enables the assessment of the sensitivity of [11C]SKF dopamine D1 binding to changes in endogenous dopamine levels.