In vivo evaluation of [11C]SA4503 as a PET ligand for mapping CNS sigma1 receptors

Kawamura, Kazunori; Ishiwata, Kiichi; Tajima, Hiromi; Ishii, Shin‐ichi; Matsuno, Kiyoshi; Homma, Yoshio; Senda, Michio

doi:10.1016/s0969-8051(00)00081-0

Cited by 99 publications

(94 citation statements)

References 27 publications

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“…Measured occupancy values can be subsequently compared with the dose-dependent effects of test drugs on cellular morphology and growth. The s-1 agonist SA4503, labeled with the positron emitter 11 C, is available for this purpose (19). We used C6 cells as an in vitro model for the measurement of both s-receptor occupancy and cytotoxic effects.…”

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confidence: 99%

Cytotoxicity of σ-Receptor Ligands Is Associated with Major Changes of Cellular Metabolism and Complete Occupancy of the σ-2 Subpopulation

Rybczynska¹,

Dierckx²,

Ishiwata³

et al. 2008

J Nucl Med

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Tumor cells can be selectively killed by application of s-ligands; high concentrations (20-100 mM) are often required, however, because either diffusion barriers must be passed to reach intracellular sites or the entire s-receptor population should be occupied to induce cell death. We measured receptor occupancies associated with the cytotoxic effect and dose-dependent changes of cellular metabolism in a tumor cell line. Methods: C6 cells (rat glioma) were grown in monolayers and exposed to (1)-pentazocine (s-1 agonist), AC915 (s-1 antagonist), rimcazole (s-1/s-2 antagonist), or haloperidol (s-1/s-2 antagonist). Occupancy of s-receptors by the test drugs was measured by studying the competition of the test drugs with cellular binding of the ligand 11 C-SA4503. Metabolic changes were quantified by measuring cellular uptake of 18 F-FDG, 18 F-FLT, 11 C-choline, or 11 Cmethionine. Cytotoxicity was assessed by cellular morphology observation and cell counting after 24 h. Results: IC 50 values (drug concentrations resulting in 50% occupancy of the available binding sites) of the test drugs for inhibition of cellular 11 C-SA4503 binding were 6.5, 7.4, 0.36, and 0.27 mM for (1)-pentazocine, AC915, rimcazole, and haloperidol, respectively. EC 50 values (dose required for a 50% reduction of cell number after 24 h) were 710, 819, 31, and 58 mM, for pentazocine, AC915, rimcazole, and haloperidol, respectively. Cytotoxic doses of s-ligands were generally associated with increased uptake of 18 F-FDG, decreased uptake of 18 F-FLT and 11 C-choline, and little change in 11 C-methionine uptake per viable cell. Conclusion: IC 50 values of the test drugs reflect their in vitro affinities to s-2 rather than to s-1 receptors. Because cytotoxicity occurred at concentrations 2 orders of magnitude higher than IC 50 values for inhibition of cellular 11 C-SA4503 binding, high (99%) occupancy of s-2 receptors is associated with loss of cell viability. 18 F-FLT, 11 C-choline, and 18 F-FDG responded most strongly to drug treatment and showed changes corresponding to the cytotoxicity of the test compounds.

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confidence: 99%

Cytotoxicity of σ-Receptor Ligands Is Associated with Major Changes of Cellular Metabolism and Complete Occupancy of the σ-2 Subpopulation

Rybczynska¹,

Dierckx²,

Ishiwata³

et al. 2008

J Nucl Med

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“…[32][33][34][35][36] Despite attractive features associated with PET techniques, PET studies are still limited, since they usually require on-site cyclotrons. On the other hand, SPECT studies are more commonly used in nuclear medicine clinics.…”

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Synthesis and in Vitro Evaluation of Iodinated Derivatives of Piperazine as a New Ligand for Sigma Receptor Imaging by Single Photon Emission Computed Tomography

Hirata

Mori

Soga

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…However, it is also a ligand for Û-re-Hatip-Al-Khatib/Bolukbaşi-Hatip ceptors which are reported in the myocardium [5], specifically Û 1 -receptor subtype [6]. Haloperidol also blocks cardiac (GIRK ¼) and cerebral (GIRK ½) G-protein-activated inwardly rectifying K + channels.…”

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confidence: 99%

Modulation of the Negative Inotropic Effect of Haloperidol by Drugs with Positive Inotropic Effects in Isolated Rabbit Heart

Hatip‐Al‐Khatib

Bolukbaşi-Hatip²

2002

Pharmacology

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Haloperidol is a typical antipsychotic drug with inhibitory effects on dopamine and calcium homeostasis. In this study, the effect of haloperidol on the inotropism of rabbits’ isolated heart was investigated by measuring the isovolumetric left ventricular pressure using a balloon in a modified Langendorff perfusion apparatus. Haloperidol at 0.01–0.3 µmol/l induced a negative inotropic effect (E_max = 77.95 ± 0.19; EC₅₀ = 0.043 ± 0.002 µmol/l). The effect of haloperidol was decreased by Ca²⁺ (E_max = 42.93 ± 3.22; EC₅₀ = 0.37 ± 0.07 µmol/l; pD’₂ = 7.01 ± 0.16), Bay K 8644 (E_max = 30.75 ± 1.33; EC₅₀ = 10.43 ± 1.5 µmol/l, pD’₂ = 7.13 ± 0.12), and digoxin (E_max = 42.03 ± 3.72, EC₅₀ = 0.32 ± 0.05 µmol/l, pD’₂ = 6.81 ± 0.14). The effect of haloperidol was also reduced by norepinephrine (E_max = 37.16 ± 1.84; EC₅₀ = 1.73 ± 0.24 µmol/l, pD’₂ = 6.97 ± 0.08) and dopamine (E_max = 35.68 ± 2.78; EC₅₀ = 0.69 ± 0.01 µmol/l, pD’₂7.48 ± 0.15). However, the effect of haloperidol was nonsignificantly reduced by dobutamine (E_max = 58.89 ± 5.18; EC₅₀ = 0.15 ± 0.06 µmol/l, pD’₂ = 5.88 ± 0.47). These results show that the drugs that increase the influx of Ca²⁺ into the cardiomyocyte decrease the negative inotropic effect of haloperidol, suggesting that the effect of haloperidol could be mediated via mechanisms involving actions on Ca²⁺ entry into the cardiomyocyte. Haloperidol should be used carefully when prescribed for patients with cardiovascular disorders.

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In vivo evaluation of [11C]SA4503 as a PET ligand for mapping CNS sigma1 receptors

Cited by 99 publications

References 27 publications

Cytotoxicity of σ-Receptor Ligands Is Associated with Major Changes of Cellular Metabolism and Complete Occupancy of the σ-2 Subpopulation

Cytotoxicity of σ-Receptor Ligands Is Associated with Major Changes of Cellular Metabolism and Complete Occupancy of the σ-2 Subpopulation

Synthesis and in Vitro Evaluation of Iodinated Derivatives of Piperazine as a New Ligand for Sigma Receptor Imaging by Single Photon Emission Computed Tomography

Modulation of the Negative Inotropic Effect of Haloperidol by Drugs with Positive Inotropic Effects in Isolated Rabbit Heart

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