Synthesis and in vitro affinities of various MDL 100907 derivatives as potential ¹⁸F-radioligands for 5-HT_2A receptor imaging with PET

Abstract

Radiolabelled piperidine derivatives such as [¹¹C]MDL 100907 and [¹⁸F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with ¹⁸F-fluorine, were synthesized to improve molecular imaging properties of [¹¹C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors and their lipophilicities were determined and compared to the clinically used reference compounds MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show K_i-values in the nanomolar range towards the 5-HT_2A receptor and insignificant binding to other 5-HT receptor subtypes or receptors. Interestingly, compounds MA-1 (53), MH.MZ (55) and (R)-MH.MZ (56) provide a receptor selectivity profile similar to MDL 100907. These compounds could possibly be preferable antagonistic ¹⁸F-tracers for visualization of the 5-HT_2A receptor status. Medium affine compounds (VK-1 (32), (51), (52), (54)) were synthesized and have K_i values between 30 and 120 nM. All promising compounds show log P values between 2 and 3, that is, within the range of those for the established radiotracers altanserin and MDL 100907. The novel compounds MA-1 (53) and (R)-MH.MZ (56) thus appear to be promising high affine and selective tracers of ¹⁸F-labelled analogues for 5-HT_2A imaging with PET.

Introduction

Serotonin (5-hydroxytryptamine, 5-HT), its transporter and various receptors are of central interest in the field of medicinal chemistry.1, 2, 3 Seven major families of transmembrane receptors (5-HT_1–7) and one transporter (SERT) are known to control 5-HT function by three different structures (transporters, ligand-gated ion channels and G-protein-coupled receptors).⁴ The role of 5-HT_2A receptors in the regulation of a number of processes of the central nervous system (CNS) such as mood, appetite, sexual behaviour, learning and memory and their dysfunctions such as psychosis, depression and anxiety has been well documented.5, 6 In particular, the 5-HT_2A receptors have been implicated in the beneficial effects of some antidepressants as well as antipsychotics.⁷ All clinically approved atypical antipsychotic drugs are also potent 5-HT_2A receptor antagonists.8, 9 Moreover, many hallucinogens including LSD function as agonists at 5-HT_2A receptors.⁷

Consequently, in vivo studies of 5-HT_2A receptor availability would significantly advance the understanding of the biological principles of mentioned disorders and contribute to the development of appropriate therapies. Positron emission tomography (PET) is an appropriate tool to measure in vivo directly, non-invasively and repetitively the relevant pharmacologic parameters of ligand–neuroreceptor interactions.

Supposed adequate radiolabeled neurotransmitter analogues are available for the molecular imaging of the 5-HT_2A receptor. To date, in vivo studies have been performed with several 5-HT_2A selective antagonists. Of these tracers, [¹¹C]MDL 100907 (a) and [¹⁸F]altanserin (b) represent the radioligands of choice for in vivo 5-HT_2A PET imaging because of their high affinity and selectivity for the 5-HT_2A receptor. In addition to their high binding affinities to the 5-HT_2A receptor (altanserin: K_i = 0.13 nM; MDL 100907 K_i = 0.36 nM) their binding affinities are more than 30-fold lower for other relevant receptors such as 5-HT_1A, 5-HT_2C, α₁, D₁ and D₂ (Table 1).10, 11, 12, 13, 14

In in vitro and in in vivo experiments, both tracers revealed high affinity, selectivity and a good ratio of specific to non-specific binding for 5-HT_2A receptors_.15, 16 However, Table 1 indicates that the selectivity of [¹¹C]MDL 100907 for the 5-HT_2A receptor is slightly higher than that of [¹⁸F]altanserin.¹⁵ Tracer affinity and selectivity are of crucial importance for uptake kinetics in brain, and tracers with very high affinity and selectivity give new insights into the role of the status of the serotonergic system and antipsychotic drug action. For example, Mintun et al. measured in vivo with [¹⁸F]altanserin a decreased hippocampel 5-HT_2A receptor binding in major depressive patients.¹⁷

Concerning molecular imaging, the advantage of [¹⁸F]altanserin (b) over [¹¹C]MDL 100907 (a) is the possibility to perform equilibrium scans lasting several hours and to transport the tracer to other facilities based on the 110 min half-life of ¹⁸F-fluorine.

A drawback of [¹⁸F]altanserin is its rapid and extensive metabolism. Four metabolites are formed in humans that cross the blood-brain-barrier,¹³ whereas metabolites of [¹¹C]MDL 100907 do not enter the brain to any larger extent.¹⁸

The aim of this study was to synthesize a ligand combining the reported better selectivity and in vivo stability of MDL 100907 as compared to those of altanserin and the superior isotopic properties of an ¹⁸F-label as compared to those of a ¹¹C-label.

Recently, we have reported the synthesis, first in vitro, ex vivo and in vivo evaluations of an ¹⁸F-analogue of MDL 100907, [¹⁸F]MH.MZ (c) (Fig. 1).

The promising results obtained in ex vivo and in vivo experiments19, 20 encouraged us to study structure–activity relationships of MDL 100907 analogues in more detail aiming at even improving affinity and selectivity of new compounds. Unfortunately, no detailed structure–activity relationship has been reported yet for this class of compound. A rudimental pharmacophore model has been published by Andersen et al.²¹ It describes the binding of various arylpiperidines at 5-HT₂ receptors. The model requires two aryl substituents, separated by distance a and located distances b and c from an amine moiety (Fig. 2). Distances suggested by Anderson et al. for a, b and c are 5.1, 7.5 and 8.1 Å, respectively.

Heinrich et al.²² described an optimization of the structure and the discovery of a selective 5-HT_2A antagonist, but no attempts have been made to optimize these MDL 100907 analogues for in vivo PET imaging.

Herein, we report the syntheses of new MDL 100907 analogues to enlighten structure–activity relationships. In addition, some new derivatives may be considered as potential ¹⁸F-radioligands for 5-HT_2A receptor PET imaging.