Binding characteristics of the 5‐HT2A receptor antagonists altanserin and MDL 100907

Abstract

To study the 5‐HT_2A receptors in the living human brain, using positron emission tomography (PET), two selective radiotracers are currently in use: [¹⁸F]altanserin and [¹¹C]MDL 100907. It is, however, currently unknown to what extent data obtained with either tracer are directly comparable. The aim of this study was to compare binding characteristics of these two radiotracers in rat brain with respect to affinity (K_d), receptor binding density (B_max), binding potential (BP), and nonspecific binding. Further, binding kinetics, sensitivity towards competition with the endogenous transmitter serotonin, and the competitive/noncompetitive interaction between the two radioligands were evaluated. In addition, the selectivity of [¹⁸F]altanserin for the 5‐HT_2A receptor was assessed. The K_d value of [¹⁸F]altanserin and [³H]MDL 100907 was in the order of 0.3 nM. B_max in frontal cortex was 523 and 527 fmol/mg protein, respectively. The binding of [¹⁸F]altanserin was not influenced by blocking either the 5‐HT_2B/2C or the α₁‐adrenergic receptors. At 37°C the association t_1/2 was 2.8 and 2.7 min and the dissociation t_1/2 was 11 and 13.5 min for [¹⁸F]altanserin and [³H]MDL 100907, respectively. Both radioligands were displaced by 5‐HT, only at high concentrations; the K_i value of 5‐HT ranging between 650 and 3,300 nM. This indicates that binding of both radioligands in PET studies is not directly influenced by changes in endogenous 5‐HT. Overall, the binding of [¹⁸F]altanserin and [³H]MDL 100907 to the 5‐HT_2A receptor was very comparable, showing selective high affinity binding in the subnanomolar range. Synapse 58:249–257, 2005.