Radiosynthesis, in vitro and in vivo evaluation of 8-[4-(2-[18F]fluoroethoxy)benzyl]-1,4-dioxa-8-azaspiro[4.5]decane, a spirocyclic σ1 receptor ligand for tumor targeting

Aim: Sigma (σ) receptors have a characteristic distribution in the brain and are implicated in many diseases of the central nervous system. In the past years a number of PET and SPECT radiotracers for visualization of σ‐receptors in the brain have been developed. In addition, σ‐receptors are up‐regulated in various tumor cells motivating us to develop a series of novel spirocyclic receptor ligands showing high affinity and good selectivity for σ1. One candidate was radiolabeled with fluorine‐18 as potential radiotracer for tumor targeting.
Methods: Six novel spirocyclic σ1 receptor ligands were designed, synthesized, and characterized. The affinity to σ1 and σ2 receptors was tested, one derivative, 8‐[4‐(2‐[18F]fluoroethoxy)benzyl]‐1,4‐dioxa‐8‐azaspiro[4.5]decane, was chosen for radiolabeling with fluorine‐18. The stability of the radiotracer in vitro and in vivo was evaluated, the logP value was determined. Biodistribution studies in rats and mice as well as dynamic small animal PET studies in nude mice xenografted with DU145 human prostate tumors were performed.
Results: The Ki values of the spirocyclic ligands were determined to be in the range 3.26‐11.2 nM for σ1 and 164.4‐312.2 nM for σ2. The radiotracer was prepared by 18F‐fluoroethylation of the corresponding hydroxyl precursor via a two‐step automated procedure in 20% yield and 99% radiochemical purity with a specific activity about 45 GBq/μmol. The logP value was determined 0.81 ± 0.13, and it was found to be stable in vitro in saline, ethanol, and human plasma. Biodistribution in normal mice and Wistar rats showed radiotracer uptake in σ1‐rich regions like brain and pancreas that could be blocked by pre‐administration of haloperidol. In mice fast degradation of the radiotracer
resulting in four metabolites was observed. However, PET studies in mouse tumor models showed tumor uptake of about 0.77+/‐0.45 (SUV, 1 h p.i.), which likewise could be substantially blocked by haloperidol.
Conclusion: We have developed an 18F‐labeled spirocyclic receptor ligand with high selectivity for σ1 and excellent hydrophilicity. We demonstrated by successful PET imaging in mice bearing σ1‐expressing DU‐145 tumors the principle of targeting tumors with radiolabeled σ‐ligands. However, the unfavorable in vivo stability of this spirocyclic derivative limits a broader application as an imaging agent.