The development of radiotracers for imaging sigma (σ) receptors in the central nervous system (CNS) using positron emission tomography (PET).

Sigma (σ) receptors are unique mammalian proteins, distributed in the central nervous system and elsewhere, which are increasingly implicated in the pathophysiology of virtually all major central nervous system disorders. The heterogeneous but wide distribution of σ1 in the brain has prompted the development of selective radiotracers for imaging these sites using positron emission tomography (PET). To date, some 50 carbon-11-labelled and fluorine-18-labelled candidate PET radioligands targeting σ receptors have been reported. The historical development of selective σ1 receptor ligands as potential PET imaging agents, as well as the radiochemistry and application of the most recently developed examples, is described herein.

N-substituted 8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes as σ receptor ligands with potential neuroprotective effects.

Several libraries of similarly N-substituted 8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes (9), N-methyl-8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes (14), and N-methyl-11-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecan-8-ones (13) were synthesised and screened against a panel of CNS targets in order to develop structure-affinity relationships for cage-modified trishomocubane σ receptor ligands based on the N-substituted 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (8) scaffold. In general, compared to the corresponding 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols, compounds of type 9 were potent σ receptor ligands with low levels of subtype selectivity, while the corresponding N-methyl-8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes showed reduced affinity but greater selectivity for σ2 receptors. The N-methyl-11-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecan-8-ones demonstrated the poorest σ receptor affinities, suggesting that 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols interact with σ receptors in the bridged hemiaminal form rather than as the non-transannular, aminoketone tautomers. Several compounds of type 8, 9, and 14 were assessed for their ability to inhibit nitric oxide release in vitro, and demonstrated comparable or greater efficacy than 4-phenyl-1-(4-phenylbutyl)piperidine (PPBP), an established neuroprotective σ ligand with NOS inhibitory activity.

A σ(1) receptor pharmacophore derived from a series of N-substituted 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols (AHDs).

A library of N-substituted 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols (AHDs) was synthesized and subjected to competition binding assays at σ(1) and σ(2) receptors, as well as off-target screening of representative members at 44 other common central nervous system (CNS) receptors, transporters, and ion channels. Excluding 3 low affinity analogs, 31 ligands demonstrated nanomolar K(i) values for either σ receptor subtype. Several selective σ(1) and σ(2) ligands were discovered, with selectivities of up to 29.6 times for σ(1) and 52.4 times for σ(2), as well as several high affinity, subtype non-selective ligands. The diversity of structures and σ(1) affinities of the ligands allowed the generation of a σ(1) receptor pharmacophore that will enable the rational design of increasingly selective and potent σ(1) ligands for probing σ(1) receptor function.

Exploration of ring size in a series of cyclic vicinal diamines with σ1 receptor affinity.

Imidazolidine and 1,4-diazepane analogs of N-(2-benzofuranyl)methyl-N'-(4-alkoxybenzyl)piperazines were prepared to explore the effect of ring contraction and expansion on σ receptor affinity and subtype selectivity within a series of cyclic diamines. In vitro receptor binding assays revealed that all cyclic vicinal diamines possessed affinity and selectivity for σ(1) receptors. The imidazolidines possessed nanomolar σ(1) affinities (K(i)=6.45-53.5 nM), and relatively low levels of subtype selectivity (σ(2)/σ(1)=58-237). However, the piperazines and diazepanes achieved picomolar σ(1) interactions, with K(i) ranges of 0.05-10.28 and 0.10-0.194 nM, respectively. Moreover, the piperazines and diazepanes showed excellent discrimination over the σ(2) receptor, with σ(1) selectivities of 143-16140 and 220-11542, respectively.