Abstract
1143
Objectives: To identify radioiodinated sigma-1 receptor ligands that exhibit a high level of specific, but reversible, binding to cerebral and peripheral sites in vivo. Methods: The E- and Z-isomers of N-iodoallyl-dimethoxyphenethylpiperazine (E-1 and Z-1) were prepared by standard methodology. Binding assays (guinea pig brain membranes) were done against [3H](+)-pentazocine for sigma-1 sites, and [3H]-DTG / 200 nM (+)-pentazocine for sigma-2 sites. [125I]-E-1 and Z-1 were prepared at high specific activity by iododestannylation, and used for Log D7.4 measurements, in vivo studies in male CD1 mice, and ex vivo quantitative autoradiography. Results: In vitro, E-1 displayed moderately high affinity for sigma-1 sites (Ki = 15.1 ± 1.3 nM) and 84-fold selectivity against sigma-2 sites (Ki = 1263 ± 166 nM). Z-1 gave similar sigma-1 affinity (Ki = 19.9 ± 1.3 nM), but lower selectivity (23-fold) over sigma-2 sites (Ki = 455 ± 66 nM). Log D7.4 values ([125I]-E-1, 2.25 ± 0.008; [125I]-Z-1, 2.27 ± 0.006; n = 5) proved optimal for brain penetration. In vivo, [125I]-E-1 exhibited higher mouse brain uptake and longer retention than the Z-isomer, with 5.8% ± 1.2 %ID/g at 15 min clearing as a single exponential (r2 = 0.99) to 1.5% ± 0.1 %ID/g by 120 min. Pretreatments (2.5 ?mol/kg) with cold E-1, haldol (sigma-1, sigma-2), BD1063 (sigma-1) and a bromobenzamide (sigma-2) showed that [125I]-E-1 selectively labels sigma-1 receptors throughout mouse brain and periphery with a high level of specific binding (ca. 80 - 90%; 60 min). For 15 brain regions, ex vivo autoradiography (60 min) showed correlation (r = 0.89, p < 0.0001) with literature data from a similar [3H]-SKF 10,047 study. Conclusions: [125I]-E-1 exhibits moderate affinity and good selectivity for sigma-1 receptors, reaches pseudo-equilibrium in vivo in mouse brain and periphery, and displays a high level of specific binding. These properties are amenable to in vivo occupancy studies of non-radioactive sigma-1 ligands, and suggest that [123I]-E-1 has potential for SPECT imaging of central and peripheral sigma-1 receptors.
Research Support (if any): NIH P50 CA103130: Center for Single Photon-Emitting Cancer Imaging Agents
- Society of Nuclear Medicine, Inc.