Synthesis and biological evaluation of ¹⁸F labeled fluoro-oligo-ethoxylated 4-benzylpiperazine derivatives for sigma-1 receptor imaging.

We report the synthesis and evaluation of a series of fluoro-oligo-ethoxylated 4-benzylpiperazine derivatives as potential σ(1) receptor ligands. In vitro competition binding assays showed that 1-(1,3-benzodioxol-5-ylmethyl)-4-(4-(2-fluoroethoxy)benzyl)piperazine (6) exhibits low nanomolar affinity for σ(1) receptors (K(i)=1.85 ± 1.59 nM) and high subtype selectivity (σ(2) receptor: K(i)=291 ± 111 nM; K(i)σ(2)/K(i)σ(1)=157). [(18)F]6 was prepared in 30-50% isolated radiochemical yield, with radiochemical purity of >99% by HPLC analysis after purification, via nucleophilic (18)F(-) substitution of the corresponding tosylate precursor. The logD(pH 7.4) value of [(18)F]6 was found to be 2.57 ± 0.10, which is within the range expected to give high brain uptake. Biodistribution studies in mice demonstrated relatively high concentration of radiotracers in organs known to contain σ(1) receptors, including the brain, lungs, kidneys, heart, and spleen. Administration of haloperidol 5 min prior to injection of [(18)F]6 significantly reduced the concentration of radiotracers in the above-mentioned organs. The accumulation of radiotracers in the bone was quite low suggesting that [(18)F]6 is relatively stable to in vivo defluorination. The ex vivo autoradiography in rat brain showed high accumulation of radiotracers in the brain areas known to possess high expression of σ(1) receptors. These findings suggest that [(18)F]6 is a suitable radiotracer for imaging σ(1) receptors with PET in vivo.