PET imaging of σ1 receptors: New F-18-labelled alkyl-substituted spirocyclic piperidine radiotracers

Fragestellung
There is evidence that σ1 receptors are involved in the cognitive impairment found in neurodegenerative diseases. Because of considerable drawbacks of the currently used PET ligand for neuroimaging of σ1 receptors, [C-11]SA4503, we have recently developed a new spirocyclic piperidine derivative: [F-18]WMS1813 ([F-18]1'-benzyl-3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4'-piperidine]) with high affinity and selectivity for σ1 receptor binding site (1). Further SAR studies on the fluoroalkyl chain provided three other promising analogues, bearing either fluoromethyl- (WMS1850), fluoroethyl- (WMS1828) or fluorobutyl-(WMS1847) moieties. Herein, we report on radiosyntheses and biological evaluation of these candidates for PET imaging of σ1 receptors.

Methodik
Radiosyntheses of [F-18]WMS1850, [F-18]WMS1828, and [F-18]WMS1847 were performed by direct nucleophilic substitution of corresponding aliphatic tosylate precursors, using the K[F-18]F-K222-carbonate complex. Biodistribution studies and ex vivo brain autoradiography of the radiotracers were performed in female CD-1 mice. Target specificity was validated by pre-treatment with 1 mg/kg i.p. of the σ1 receptor antagonist haloperidol. In vivo metabolism of each radiotracer was evaluated by radio- TLC/-HPLC.

Ergebnis
The three radiotracers were obtained with radiochemical yields of 35-53%, radiochemical purities >98.5%, and high specific activities ≥150 GBq/μmol. In mice, they rapidly accumulated in brain tissue. [F-18]WMS1828 was superior with a brain uptake value of 4.71 ± 1.39 %ID/g (30 min p.i.) in comparison to [F-18]WMS1813, [F-18]WMS1847 and [F-18]WMS1850 (3.18±0.68; 1.78±0.16; 2.65±0.68 %ID/g respectively). For all radiotracers, uptake in brain as well as in peripheral σ1 receptor expressing organs was significantly inhibited by haloperidol. At 30 min p.i., more than 75% of the radioactivity detected in plasma samples corresponded to native [F-18]WMS1850, [F-18]WMS1828 and [F-18]WMS1847. None of the radiometabolites observed crossed the blood-brain barrier. Results of ex vivo autoradiography of brain slices revealed resemblance between radioactivity distribution pattern of all radiotracers and regions with known high σ1 receptors density. The highest target (facial nucleus)-to-nontarget (olfactory bulb) tissue ratio was determined for [F-18]WMS1828 (4.69 at 45 min p.i.).

Schlussfolgerungen
Within the series of σ1 receptor-specific radiotracers studied, [F-18]WMS1828 ([F-18]fluspidine) appears to be the most promising candidate for PET imaging with even better pharmacological profile than the lead compound WMS1813. Hence, [F-18]fluspidine radiosynthesis is selected for transfer onto an automated radiosynthesis module for further (pre)clinical development.

Literatur
(1) Maestrup E G et al. J Med Chem 2009; 52, 6062-6072.