Synthesis and evaluation of 11C- and 18F-labeled 1-[2-(4-alkoxy-3-methoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazines as sigma receptor ligands for positron emission tomography studies

Kawamura, Kazunori; Elsinga, Philip H.; Kobayashi, Toshimichi; Ishii, Shin‐ichi; Wang, Weifang; Matsuno, Kiyoshi; Vaalburg, W; Ishiwata, Kiichi

doi:10.1016/s0969-8051(02)00439-0

Cited by 52 publications

(44 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…11 C-SA4503 was made by reaction of 11 C-methyl iodide with the appropriate 4-O-methyl compound (15). The decay-corrected radiochemical yield was 9%-11%, and the specific radioactivity was greater than 11 TBq/mmol at the time of injection.…”

Section: Methodsmentioning

confidence: 99%

Rapid Reduction of 1-Receptor Binding and 18F-FDG Uptake in Rat Gliomas After In Vivo Treatment with Doxorubicin

Waarde¹,

Shiba²,

Jong³

et al. 2007

Journal of Nuclear Medicine

View full text Add to dashboard Cite

Section: Methodsmentioning

confidence: 99%

Rapid Reduction of 1-Receptor Binding and 18F-FDG Uptake in Rat Gliomas After In Vivo Treatment with Doxorubicin

Waarde¹,

Shiba²,

Jong³

et al. 2007

Journal of Nuclear Medicine

View full text Add to dashboard Cite

“…11 C-SA4503 was prepared by reaction of 11 C-methyl iodide with the appropriate 4-O-methyl precursor (26). Specific radioactivity at the end of synthesis was greater than 22 TBq/mmol.…”

Section: Radiopharmaceuticalsmentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…The radioligand 11 C-SA4503 was prepared by reaction of 11 C-methyl iodide with 1-[2-(4-hydroxy-3-methoxy-penthyl)]-4-(3-phenylpropyl)piperazine dihydrochloride (4-O-demethyl SA4503), according to a published method (27). The decay-corrected radiochemical yield was about 24%, the specific radioactivity was greater than 100 TBq/mmol at the moment of injection, and radiochemical purity was greater than 98%.…”

Section: C-sa503 Synthesismentioning

confidence: 99%

Small-Animal PET with a σ-Ligand, ¹¹C-SA4503, Detects Spontaneous Pituitary Tumors in Aged Rats

et al. 2013

Self Cite

View full text Add to dashboard Cite

Pituitary tumors are often detected only after death or at late stages of the disease when they are macroadenomas with a low surgical cure rate. Spontaneous pituitary tumors occur in rats over 1 y of age. In an ongoing study of changes in s-1 agonist binding related to aging, several of our rats developed such tumors. The aim of the current study was to assess the kinetics of 11 C-SA4503 ( 11 C-labeled 1-[2-(3,4-dimethoxyphenthyl)]-4-(3-phenylpropyl)-piperazine dihydrochloride) in tumor and brain and to evaluate the utility of this tracer in the detection of pituitary tumors. Methods: Small-animal PET scans of the brain region of male Wistar Hannover rats (age, 18-32 mo) were acquired using the s-1 agonist tracer 11 C-SA4503. The time-dependent uptake of 11 C in the entire brain, tumor or normal pituitary, and thyroid was measured. A 2-tissue-compartment model was fitted to the PET data, using metabolite-corrected plasma radioactivity as the input function. Results: Pituitary tumors showed up as bright hot spots in the scans. The total distribution volume (V T ) of the tracer was significantly higher in the tumor than in the normal pituitary. Surprisingly, a higher V T was also seen in the brain and thyroid tissue of animals with pituitary tumors than in healthy rats. The increase in V T in the brain and thyroid was not related to a change in nondisplaceable binding potential (BP ND ) but rather to an increase in the partition coefficient (K 1 /k 2 ) of 11 C-SA4503. The increase in V T in the tumor on the other hand was accompanied by a significant increase in BP ND . Western blotting analysis indicated that pituitary tumors overexpressed s-1 receptors. Conclusion: The overexpression of s-1 receptors in spontaneous pituitary tumors is detected as an increase in uptake and BP ND of 11 C-SA4503. Therefore, this tracer may have promise for the detection of pituitary adenomas, using PET.

show abstract

Synthesis and evaluation of 11C- and 18F-labeled 1-[2-(4-alkoxy-3-methoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazines as sigma receptor ligands for positron emission tomography studies

Cited by 52 publications

References 29 publications

Rapid Reduction of 1-Receptor Binding and 18F-FDG Uptake in Rat Gliomas After In Vivo Treatment with Doxorubicin

Rapid Reduction of 1-Receptor Binding and 18F-FDG Uptake in Rat Gliomas After In Vivo Treatment with Doxorubicin

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

Small-Animal PET with a σ-Ligand, ¹¹C-SA4503, Detects Spontaneous Pituitary Tumors in Aged Rats

Contact Info

Product

Resources

About

Synthesis and evaluation of 11C- and 18F-labeled 1-[2-(4-alkoxy-3-methoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazines as sigma receptor ligands for positron emission tomography studies

Cited by 52 publications

References 29 publications

Rapid Reduction of 1-Receptor Binding and 18F-FDG Uptake in Rat Gliomas After In Vivo Treatment with Doxorubicin

Rapid Reduction of 1-Receptor Binding and 18F-FDG Uptake in Rat Gliomas After In Vivo Treatment with Doxorubicin

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

Small-Animal PET with a σ-Ligand, 11C-SA4503, Detects Spontaneous Pituitary Tumors in Aged Rats

Contact Info

Product

Resources

About

Small-Animal PET with a σ-Ligand, ¹¹C-SA4503, Detects Spontaneous Pituitary Tumors in Aged Rats