Synthesis and in vivo evaluation of a PET radioligand for imaging the endothelin-A receptor

Mathews, William B.; Zober, Tamas G.; Ravert, Hayden T.; Scheffel, Ursula; Hilton, John; Sleep, Darryl J.; Dannals, Robert F.; Szabó, Zsolt

doi:10.1016/j.nucmedbio.2005.07.012

Cited by 7 publications

(6 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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). The target organ is the heart.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Mathews

Murugesan

Xia³

et al. 2008

J Nucl Med

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The specific activity of 11 C-PD156707, however, was low, and this radioligand has not been used for in vivo imaging. ETA selective radioligands with improved binding characteristics have been synthesized (21)(22)(23), but thus far, none has been used for imaging endothelin receptors in humans.…”

mentioning

confidence: 99%

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

Mathews

Murugesan

Xia³

et al. 2008

J Nucl Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Based on non-peptidic, small molecular antagonists against either ET A R alone or ET A R and ET B R, there have been a number of developments (e.g. 18 F-SB209670, 11 C-Atrasentan, 18 F-FBzBMS or 18 F-PD156707) for the non-invasive in vivo imaging of ET receptor distribution, mainly for scintigraphic imaging (3,42,43,52,66,70).…”

Section: Endothelin Receptors For Imaging Of Endothelial Functionmentioning

confidence: 99%

Optical imaging probes and their potential contribution to radiotracer development

Faust¹,

Hermann²,

Schäfers³

et al. 2016

Nuklearmedizin

View full text Add to dashboard Cite

Optical imaging has long been considered a method for histological or microscopic investigations. Over the last 15 years, however, this method was applied for preclinical molecular imaging and, just recently, was also able to show its principal potential for clinical applications (e .g. fluorescence-guided surgery). Reviewing the development and preclinical evaluation of new fluorescent dyes and target-specific dye conjugates, these often show characteristic patterns of their routes of excretion and biodistribution, which could also be interesting for the development and optimization of radiopharmaceuticals. Especially ionic charges show a great influence on biodistribution and net-charge and charge-distribution on a conjugate often determines unspecific binding or background signals in liver, kidney or intestine, and other organs. Learning from fluorescent probe behaviour in vivo and translating this knowledge to radiopharmaceuticals might be useful to further optimize emerging and existing radiopharmaceuticals with respect to their biodistribution and thereby availability for binding to their targets.

show abstract

“…26,27 The in vivo visualization of the ET system in affected tissue with scintigraphic techniques, such as positron emission tomography (PET), would be highly valuable for clinical diagnosis and evaluation of therapy. Different ET receptor ligands have been developed, radiolabeled by [ 11 C]methylation or [ 18 F]fluorination, and utilized for PET imaging of the ET receptor distribution in a baboon, 28 dog, 29 and rats. 30 However, up to now, none of these approaches have been applied to in vivo imaging of ET receptors in humans.…”

Section: Introductionmentioning

confidence: 99%

“…The orally bioavailable ET A receptor antagonist (2 R ,3 R ,4 S )-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (atrasentan, ABT-627) has been shown to inhibit the growth of ovarian and cervix carcinoma cell xenografts , and to be effective in patients with advanced androgen-refractory prostate carcinoma. , The in vivo visualization of the ET system in affected tissue with scintigraphic techniques, such as positron emission tomography (PET), would be highly valuable for clinical diagnosis and evaluation of therapy. Different ET receptor ligands have been developed, radiolabeled by [ 11 C]methylation or [ 18 F]fluorination, and utilized for PET imaging of the ET receptor distribution in a baboon, dog, and rats . However, up to now, none of these approaches have been applied to in vivo imaging of ET receptors in humans.…”

Section: Introductionmentioning

confidence: 99%

Development and Evaluation of Endothelin-A Receptor (Radio)Ligands for Positron Emission Tomography

et al. 2011

View full text Add to dashboard Cite

The expression and function of endothelin (ET) receptors are abnormal in cardiovascular diseases, tumor progression, and tumor metastasis. A previously reported promising radioligand for positron emission tomography (PET) based on the non-peptide ET(A) receptor antagonist PD 156707 showed specific binding to target receptors in the myocardium but high accumulation in bile and intestine, probably because of its high lipophilicity. In this study we describe the synthesis of a series of fluorinated derivatives with hydrophilic building blocks. All compounds were evaluated as high affinity ET(A) receptor ligands (16, 17, 23-26, K(i) = 1.4-7.9 nM) with high subtype selectivity over the ET(B) receptor. [(18)F]3-Benzo[1,3]dioxol-5-yl-4-{3-[1-(2-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}ethyl)-1H-[1,2,3]triazol-4-ylmethoxy]-4,5-dimethoxybenzyl}-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one ([(18)F]17) was synthesized as one of the radioligands of this series that possesses a higher hydrophilicity and an excellent stability in human serum. Improved clearance properties and specific uptake in target organs have been confirmed by biodistribution studies and small animal PET imaging.

show abstract

Synthesis and in vivo evaluation of a PET radioligand for imaging the endothelin-A receptor

Cited by 7 publications

References 15 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

Optical imaging probes and their potential contribution to radiotracer development

Development and Evaluation of Endothelin-A Receptor (Radio)Ligands for Positron Emission Tomography

Contact Info

Product

Resources

About