Radioiodinated endothelin-1: a radiotracer for imaging endothelin receptor distribution and occupancy

Gibson, Raymond E.; Fioravanti, Christine; Francis, Barbara; Burns, H. Donald

doi:10.1016/s0969-8051(98)00085-7

Cited by 10 publications

(7 citation statements)

References 22 publications

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“…These ligands may also be substrates for the p-glycoprotein pump. High specific binding in the lungs, kidneys, and heart also agrees with the known density of endothelin receptors in these organs as measured in rats (15).…”

Section: Discussionsupporting

confidence: 84%

“…Radioactivity in the liver washed out over time, and uptake in the lungs and heart remained relatively stable. This uptake corresponds to the known density of endothelin receptors as measured in rats (15). Despite its lower lipophilicity, 18 F-FBzBMS 5 showed higher liver uptake than did 11 C-BMS-5p 3, even at later time points.…”

Section: Discussionsupporting

confidence: 75%

“…The first radiotracers for endothelin either were nonselective (15)(16)(17)(18) or were synthesized at relatively low specific activity (19). Selective radioligands with improved binding characteristics have since been synthesized (21-23) but in some cases showed unfavorable metabolism in vivo (22).…”

Section: Discussionmentioning

confidence: 99%

“…The nonselective agonist peptide endothelin-1 has been labeled with both radioiodine (15) and 18 F (16). The nonselective antagonist L-753,037 was labeled with 11 C (17) and used for PET imaging of endothelin receptors in a dog (18).…”

mentioning

confidence: 99%

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Synthesis and In Vivo Evaluation of Novel PET Radioligands for Imaging the Endothelin-A Receptor

Mathews

Murugesan

Xia³

et al. 2008

J Nucl Med

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The endothelin subtype-A (ETA) receptor is a member of a family of G-protein-coupled receptors that plays a central role in vasoconstriction, cell proliferation, and hormone production. The aim of this study was to synthesize and evaluate in vivo 11 C-and 18 F-labeled analogs of the potent and selective ETA antagonist N- [[29-[[(4,5-dimethyl-3-isoxazolyl) ,3,3-trimethylbutanamide (BMS-207940). Methods: Protected precursors and authentic nonradioactive standards were synthesized by reductive amination and subsequent alkylation of protected aldehyde 1. Desmethyl precursor 2 was reacted with 11 C-methyl iodide followed by deprotection and high-performance liquid chromatography purification to produce 11 C-(N-[[29-[[(4,5-Nitro precursor 4 was reacted with 18 F-fluoride and purified by high-performance liquid chromatography to produce 18 F-(N-[[29-[[(4,5-Biodistribution was determined by injecting male CD-1 mice via the tail vein with either 11 C-BMS-5p 3 or 18 F-FBzBMS 5. Specific binding was determined by pretreatment with 1 mg of BMS-207940 per kilogram. PET scanning of a baboon using either 11 C-BMS-5p 3 or 18 F-FBzBMS 5 was performed at baseline and 40 min after intravenous administration of 1 mg of BMS-207940 per kilogram. Results: 11 C-BMS-5p 3 was synthesized with 1.5% radiochemical yield in 36 min, with an average specific activity of 1,051 GBq/mmol (28,400 mCi/mmol; n 5 5) at the end of synthesis. 18 F-FBzBMS 5 was synthesized with 0.54% radiochemical yield in 130 min, with an average specific activity of 12.9 GBq/mmol (349 mCi/mmol, n 5 7) at the end of synthesis. In mice, the highest uptake of both radioligands was in the liver, lungs, and heart. Radioactivity in the liver washed out over time, and uptake in the lungs and heart remained relatively stable. Mice pretreated with 1 mg of BMS-207940 per kilogram showed greater than 64% specific binding in the lungs and kidneys at 60 min. Specific binding in the heart was determined to be 63% for 11 C-BMS-5p 3 and 81% for 18 F-FBzBMS 5. PET studies in a baboon showed high uptake of both radioligands in the myocardium. Between 35 and 85 min, the heart-to-blood ratio was 4.7 to 1. Pretreatment with a 1 mg/kg dose of BMS-207940 showed 85% specific binding in the myocardium at 85 min after injection. Conclusion: Both 11 C-BMS-5p 3 and 18 F-FBzBMS 5 bind selectively to the ETA receptor in vivo. Further development of these radioligands for imaging the ETA receptor in humans is warranted.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Synthesis and In Vivo Evaluation of Novel PET Radioligands for Imaging the Endothelin-A Receptor

Mathews

Murugesan

Xia³

et al. 2008

J Nucl Med

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“…In kidney, there was an initial fast accumulation of radioactivity that rapidly reached equilibrium within 10 min similar to the time–activity curve in the lung; the distribution in vivo was comparable to the pattern visualised in vitro in this and previous studies (Davenport et al ., 1991) consistent with receptor binding. Treatment with the antagonist caused a significant reduction of uptake, in agreement with the ET B receptor being the predominant subtype (Gellai et al ., 1994), to levels comparable to those obtained previously with BQ788 (Fukuroda et al ., 1994; Gibson et al ., 1999). However, after ∼20 min, a slow increase in radioactivity was detected within the kidney.…”

Section: Discussionmentioning

confidence: 99%

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

Johnström

Fryer

Richards

et al. 2005

British J Pharmacology

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1 Our aim was to synthesise an 18 F analogue of endothelin-1 (ET-1), to dynamically image ET receptors in vivo by positron emission tomography (PET) and to elucidate the function of the ET B subtype as a clearing receptor in organs expressing high densities including kidney and lung. 18 F]-ET-1 in anaesthetised rats was measured using a dedicated small animal PET scanner (microPET) and ex vivo analysis. 4 Dynamic PET data demonstrated that high levels of radioligand accumulated rapidly in the lung, kidney and liver, consistent with receptor binding. The in vivo distribution correlated with the anatomical localisation of receptors detected in vitro using [ 125 I]-ET-1. However, the receptor density visualised in the heart was unexpectedly low compared with that predicted from the in vitro measurements. [18 F]-ET-1 binding in lungs could not be displaced by the ET B selective antagonist BQ788, in agreement with the proposed internalisation of ET-1 by ET B receptors. In contrast, infusion of BQ788 prior to injecting [18 F]-ET-1 significantly reduce the amount of radioligand visualised in the ET B rich lung and kidney by 85% (Po0.05, n ¼ 3) and 55% (Po0.05, n ¼ 3), respectively. 6 Under conditions of ET B receptor blockade, the heart could be visualised by microPET imaging. 7 These results suggest that clearance by ET B receptors in the lung and kidney prevents binding of ET-1 to receptors in the heart.

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Radiosynthesis of a potent endothelin receptor antagonist: [11C] L-753,037

Ravert

Mathews

Hamill

et al. 2000

J. Labelled Cpd. Radiopharm.

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Radioiodinated endothelin-1: a radiotracer for imaging endothelin receptor distribution and occupancy

Cited by 10 publications

References 22 publications

Synthesis and In Vivo Evaluation of Novel PET Radioligands for Imaging the Endothelin-A Receptor

Synthesis and In Vivo Evaluation of Novel PET Radioligands for Imaging the Endothelin-A Receptor

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

Radiosynthesis of a potent endothelin receptor antagonist: [11C] L-753,037

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Radioiodinated endothelin-1: a radiotracer for imaging endothelin receptor distribution and occupancy

Cited by 10 publications

References 22 publications

Synthesis and In Vivo Evaluation of Novel PET Radioligands for Imaging the Endothelin-A Receptor

Synthesis and In Vivo Evaluation of Novel PET Radioligands for Imaging the Endothelin-A Receptor

Positron emission tomography using 18F‐labelled endothelin‐1 reveals prevention of binding to cardiac receptors owing to tissue‐specific clearance by ETB receptors in vivo

Radiosynthesis of a potent endothelin receptor antagonist: [11C] L-753,037

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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