[3H]Spiroxatrine: A 5‐HT1A Radioligand with Agonist Binding Properties

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Abstract
Spiroxatrine has been reported to be a 5‐HT1A serotonin receptor antagonist. Therefore [3H]spiroxatrine was synthesized and its 5‐HT1A receptor binding properties in homogenates of rat hippocampal membranes were characterized with the expectation that it would be the first 5‐HT1A antagonist radioligand. [3H]8‐Hydroxydipropylaminotetralin ([3H]8‐OH‐DPAT), a well‐characterized 5‐HT1A agonist radioligand, was studied in parallel for comparative purposes. Scatchard analyses of saturation studies of [3H]spiroxatrine and [3H]8‐OH‐DPAT binding produced KD values of 0.9 nAf and 1.8 nM, with Bmax values of 424 and 360 fmol/mg protein, respectively. A highly significant correlation (r= 0.98; p < 0.001) exists between K1 values obtained for a series of drugs in competing for [3H]‐spiroxatrine and [3H]8‐OH‐DPAT binding. Of special interest was the observation that 5‐HT1A agonists such as serotonin, 8‐OH‐DPAT, and ipsapirone competed with equal high affinities for [3H]spiroxatrine or [3H]8‐OH‐DPAT‐labelled 5‐HT1A receptors. [3H]Spiroxatrine and [3H]8‐OH‐DPAT binding to 5‐HT1A receptors was inhibited by guanosine 5′‐(β,γ‐imido)triphosphate (a nonhydrolyzable analog of GTP) in a concentration‐dependent manner whereas adenosine 5′‐(β,γ‐imido)triphosphate (a non‐hydrolyzable analog of ATP) had no effect. The similarities in the 5‐HT1A receptor radiolabelling properties of [3H]‐spiroxatrine and [3H]8‐OH‐DPAT, i.e., the high affinities of agonists and the guanyl nucleotide sensitivity, indicate that [3H]spiroxatrine has “agonist‐like” binding properties in its interaction with the 5‐HT1A receptor.