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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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[18F]SB209670

Created: ; Last Update: March 25, 2007.

Chemical name:[18F]SB209670image 24271766 in the ncbi pubchem database
Abbreviated name:
Synonym:
Agent Category:Compound
Target:ET receptor
Target Category:Receptor binding
Method of detection:PET
Source of signal:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Endothelin (ET)-1 is a polypeptide of 21 amino acids and contains two disulfide bonds located close to the N-terminus. ET-1 is believed to have an important role in a variety of physiological processes and contributes to the development of diseases such as atherosclerosis, hypertension, chronic heart failure, pulmonary hypertension, acute and chronic renal failure, etc (1-3). All of these effects are mediated through a receptor-ligand interaction. Two ET receptors, ETA and ETB, have been identified in mammals (4, 5).Each receptor type is expressed in a variety of tissues and some tissues express both types (6). Various cytokines are known to regulate ET-I expression under physiological conditions (1).

In humans, stimulation of the ETA receptors by ET-I on underlying smooth muscles of the endothelium causes vasoconstriction that leads to an elevation of blood pressure and the development of hypertension (7, 8). Stimulation of the ETB receptors on the endothelium itself results in the release of nitric oxide and prostacyclins, which culminates in vasodilation (9). Because of the involvement of ET-I in a variety of physiological processes in both normal and diseased states, it is necessary to elucidate the exact in vivo role of the ET receptor system.

Positron emission tomography (PET) is a very sensitive technique, and recent improvements in equipment design have enabled researchers to use it for investigation of the ET receptor system in a small animal model (9-12). The 18F-labeled SB209670 ([18F]SB209670) ligand was developed to investigate tissue distribution of ET receptors using PET (9).

Synthesis

[PubMed]

The 18F analog of SB209670 was produced by alkylation of its precursor SB421672 with 3-[18F]fluoropropyl bromide that was prepared with 18F-labeled fluoride and 1,3-dibromopropane as described by Johnstrom et al. (9). The final product was purified by reverse-phase high-performance liquid chromatography and the solvent was evaporated for formulation in phosphate-buffered saline.

Labeled SB209670 was synthesized in 162 ± 7 min (n = 6) with a radiochemical yield of 14.9 ± 3.8% and a specific activity of 100–150 GBq/µmol (2.7–4.05 Ci/µmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The in vitro characterization of [18F]SB209670 was performed with human heart left ventricle and kidney tissues (9). For the association experiment, left ventricle sections were incubated with [18F]SB209670 for increasing time( 0–120 min) and the saturation assays were performed with increasing concentrations of [18F]SB209670 (3 pM to 10 nM) for 60 min. For the competition study, heart and kidney sections were co-incubated with a fixed concentration of [18F]SB209670 and either 1 µM FR139317, an ETA-selective antagonist, or BQ3020, (an ETB-selective antagonist.

Binding of [18F]SB209670 to the heart was concentration-dependent and saturable with a dissociation constant (KD) of 0.67 ± 0.14 nM, a Bmax of 168 ± 29.3 fmol/mg protein, and a Hill slope (nH) of 1.07 ± 0.17. The binding was time-dependent with a half-life for association (t1/2) of 3.8 min and an association rate constant (kobs) of 0.182 ± 0.032/min. This showed that the radioligand retained subnanomolar affinity for the ET receptor in the heart.

Binding of [18F]SB209670 could be inhibited partially in the kidney and almost completely in the heart by FR139317, an ETA-selective anatagonist, but not by BQ3020, an ETB-selective antagonist. Data from this experiment suggests that [18F]SB209670 binds primarily to the ETA receptor.

Animal Studies

Rodents

[PubMed]

Rats

In vivo imaging was performed in two Sprague-Dawley rats weighing 260 and 320 g, respectively (9). The animals were administered a bolus injection of 17.1 and 50.8 MBq [18F]SB209670, respectively. Specific activity of the radiotracer was ~100 GBq/µmol (2.7 Ci/ µmol) at the time of injection. PET scans were obtained for up to 120 min after injection. At the end of scanning, the animals were euthanized for ex vivo analysis of organs to determine weight and total incorporated radioactivity.

Imaging data revealed that the liver rapidly removed [18F]SB209670 from circulation with a peak at 2.5 min, then showed a fast washout that leveled to a steady state after ~50 min with no further decrease for up to 120 min. Subsequently, an increase in uptake was observed in the duodenum and jejunum of the small intestine. Uptake was also observed in the heart (data was obtained between 31 and 120 min). There was an initial increase followed by a decrease for up to 20 min, after which the label reached a steady state. Ex vivo analysis of the liver and intestine confirmed uptake by the liver and excretion primarily through the small and large intestine route. Tissue sections showed localized distribution of radioactivity in the lung, and no uptake was evident in the brain.

Observations made during in vivo scanning suggested a rapid metabolism of [18F]SB209670 by the liver, concentration of metabolites in the bile, and excretion into the small intestine. Uptake by the heart suggests binding of SB209670 to the ETA receptors. An ex vivo analysis of the lung sections revealed the binding of labeled SB209670 mainly to the vasculature that is known to contain predominantly ETA receptors. This observation was similar to an observation made earlier with 18F-labeled ET-I (10) after the ETB receptors were blocked with BQ788, an antagonist that is selective for these receptors.

Other Non-Primate Mammals

[PubMed]

No publications are currently available.

Non-Human Primates

[PubMed]

No publications are currently available.

Human Studies

[PubMed]

No publications are currently available.

References

1.
Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001;41:851–76. [PubMed: 11264479]
2.
Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu. Rev. Physiol. 1999;61:391–415. [PubMed: 10099694]
3.
Schiffrin EL, Intengan HD, Thibault G, Touyz RM. Clinical significance of endothelin in cardiovascular disease. Curr Opin Cardiol. 1997;12(4):354–67. [PubMed: 9263647]
4.
Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990;348(6303):730–2. [PubMed: 2175396]
5.
Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature. 1990;348(6303):732–5. [PubMed: 2175397]
  • 6. Davenport, AP, Distribution of endothelin receptors. Endothelins in biology and medicine., ed. JP Huggins and JT Pelton. 1997, Boca Raton: CRC Press, Inc. 45-68.
  • 7.
    de Nucci G, Thomas GR, D'Orleans-Juste P, Antunes E, Walder C, Warner TD, Vane JR. Pressor effects of circulating endothelin are limited by its removal in primary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc. Natl. Acad. Sci. USA. 1988;85(24):9797–800. [PMC free article: PMC282868] [PubMed: 3059352]
    8.
    Yokokawa K, Tahara H, Kohno M, Murakawa K, Yasunari K, Nakagawa K, Hamada T, Otani S, Yanagisawa M, Takeda T. Hyperstension associated with endothelin secreting malignant hemangioendothelioma. Ann Intern Med. 1991;114(3):213–5. [PubMed: 1984746]
    9.
    Johnstrom P, Fryer TD, Richards HK, Barret O, Clark JC, Ohlstein EH, Pickard JD, Davenport AP. In Vivo Imaging of Cardiovascular Endothelin Receptors Using the Novel Radiolabelled Antagonist [18F]-SB209670 and Positron Emission Tomography (microPET). J Cardiovasc Pharmacol. 2004;44:S34–S38. [PubMed: 15838315]
    10.
    Johnstrom P, Fryer TD, Richards HK, Harris NG, Barret O, Clark JC, Pickard JD, Davenport AP. Positron emission tomography using 18F-labelled endothelin-1 reveals prevention of binding to cardiac receptors owing to tissue-specific clearance by ET B receptors in vivo. Br J Pharmacol. 2005;144(1):115–22. [PMC free article: PMC1575985] [PubMed: 15644875]
    11.
    Johnstrom P, Harris NG, Fryer TD, Barret O, Clark JC, Pickard JD, Davenport AP. (18)F-Endothelin-1, a positron emission tomography (PET) radioligand for the endothelin receptor system: radiosynthesis and in vivo imaging using microPET Clin Sci (Lond) 2002. 103Suppl 484S–8S. [PubMed: 12193043]
    12.
    Johnstrom P, Rudd JH, Richards HK, Fryer TD, Clark JC, Weissberg PL, Pickard JD, Davenport AP. Imaging endothelin ET(B) receptors using [18F]-BQ3020: in vitro characterization and positron emission tomography (microPET). Exp Biol Med (Maywood). 2006;231(6):736–40. [PubMed: 16740990]
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