Autoradiographic Mapping of 5-HT(1B/1D) Binding Sites in the Rhesus Monkey Brain Using [carbonyl-C]zolmitriptan

Abstract

Zolmitriptan is a serotonin 5-HT(1B/1D) receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [(11)C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [(11)C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [(11)C]zolmitriptan as a radioligand. In saturation studies, [(11)C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95-5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT(1) receptor antagonists, [(11)C]zolmitriptan binding was blocked by selective 5-HT(1B) and 5-HT(1D) ligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT(1A) receptor antagonist.

Figure 1

Preparation of [carbonyl-¹¹C]zolmitriptan.

Figure 2

Color-coded autoradiograms showing Rhesus monkey whole-hemisphere autoradiography using [¹¹C]zolmitriptan. (a) Schematic drawings of the Rhesus monkey brain according to Paxinos et al. [19] to show the anterior-posterior position of the selected coronal tissue sections; (b) corresponding tissue sections; (c) autoradiograms; (d) superimposed autoradiograms and corresponding tissue sections for better anatomical localization of [¹¹C]zolmitriptan binding.

Figure 3

Color-coded autoradiograms of [¹¹C]zolmitriptan (top) and [¹¹C]WAY 100635 (bottom) on consecutive brain sections, comparing the distribution of binding sites for the respective tracer. Numbers identify sections where strong [¹¹C]zolmitriptan binding is observed. (1) Nucleus accumbens, (2) Ventral pallidum and external globus pallidus (3) Substantia nigra, and (4) Visual cortex. Note the minimal overlap of tracer binding sites.