Systemic COMT inhibition enables the D1 agonist radiotracer [11C]-(R)-SKF82957

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.