Development of a novel class of spirocyclic σ1 receptor ligands − structure-affinity relationships and fluorine-18 radiolabeling

Ziel/Aim:

Two subtypes of sigma (σ) receptors were confirmed. While the expression of σ1 is mainly altered in several brain disorders, both of them are expressed in a number of tumor entities. Some radioligands for imaging of σ1 and σ2 have been developed but most of them suffer from lipophilicity too high for tumor targeting. The aim of this study was to synthesize a series of novel spirocyclic σ1 receptor ligands, and to develop by analyzing structure-affinity relationships a suitable hydrophilic radiotracer with high affinity and selectivity for σ1.

Methodik/Methods:

A series of novel spirocyclic σ1 receptor ligands was designed, synthesized, and characterized. The affinity to σ1 and σ2 receptors was assessed and the most superior compound chosen for radiolabeling with fluorine-18. The logD value of the radiotracer, its stability in vitro and in vivo as well the biodistribution in rats were investigated.

Ergebnisse/Results:

Six spirocyclic derivatives have been synthesized; Ki values were determined to be in the range of 3.26 - 11.2 nM for σ1 and 164.4 - 312.4 nM for σ2. Compound 1 (8-[4-(2-fluoroethoxy)benzyl]-1,4-dioxa-8-azaspiro[4.5]decane; Ki σ1=5.38±0.43 nM, Ki σ2=164±20.4 nM, was selected for fluorine-18 radiolabeling. [18F]1 was prepared by fluoroethylation via a two-step automated procedure in 20% yield after column purification. The radiochemical purity was >99% as determined by HPLC analysis, the specific activity was in the range of 25 - 45 GBq/μmol. The logD value of [18F]1 was determined as 0.81±0.13. [18F]1 was stable in saline, ethanol, and human plasma in vitro for up to 2h. In preliminary experiments an uptake in mice brain of 2.6% ID at 5 min p.i. was detected.

Schlussfolgerungen/Conclusions:

We designed a potential spirocyclic σ1 receptor ligand with high affinity, selectivity, and excellent hydrophilicity. The biological evaluation of the corresponding radiotracer in brain and selected tumor models is ongoing.