Neprilysin, also known as neutral endopeptidase, is a cell surface membrane metalo-endopeptidase that cleaves various peptides. Altered neprilysin expression has been correlated with various cancers and cardiovascular diseases. In this work, we present the radiosynthesis of the novel O- C-methylated derivative of LBQ657 (a potent neprilysin inhibitor). (2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid [ C]methyl ester ([ C]MeOLBQ) is an analog of sacubitril where the alkyl ester is a C-methyl instead of an ethyl. [ C]MeOLBQ was produced in a one-pot two-step synthesis. The O- C-methylation of the pentanoic acid part was done with [ C]methyl triflate followed by the deprotection of the tert-butyl ester precursor in acidic conditions. [ C]MeOLBQ ([ C]7) was produced in 9.5 ± 2.5% RCY (25 ± 6% decay-corrected from [ C]CO , n = 3) high molar activity 348 ± 100 GBq/μmol (9425 ± 2720 mCi/μmol) at EOS, in high chemical (>95%) and radiochemical (>99%) purities. The total synthesis time including HPLC purification and reformulation was 29 minutes. To our knowledge, this is the first PET-labeled analog of the clinically used NEP inhibitor sacubitril.
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Sacubitril/valsartan reduces susceptibility to atrial fibrillation by improving atrial remodeling in spontaneously hypertensive rats.
Eur J Pharmacol
August 2023
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, PR China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, PR China. Electronic address:
Aim: Sacubitril/valsartan (Sac/Val, LCZ696), the world's first angiotensin receptor-neprilysin inhibitor (ARNi), has been widely used in the treatment of heart failure. However, the use of Sac/Val in the treatment of atrial fibrillation (AF), especially AF with hypertension, has been less reported. We investigated the effect of Sac/Val on atrial remodeling and hypertension-related AF.
View Article and Find Full Text PDFNovel O-[C]-methylated derivatives of the neprilysin inhibitor sacubitril: Radiosynthesis, autoradiography and plasma stability evaluation.
Nucl Med Biol
July 2024
Laboratoire de Radiochimie et Cyclotron, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada; Institut de Génie Biomédical, Faculté de Médecine, Université de Montréal, Pavillon Paul-G. Desmarais, 2960 chemin de la Tour, Montréal, Québec H3T 1J4, Canada; Département de Radiologie, radio-oncologie et médecine nucléaire, Faculté de médecine, Université de Montréal, Pavillon Roger-Gaudry, 2900 boulevard Edouard Montpetit, Montréal, Québec H3T 1J4, Canada. Electronic address:
Introduction: The O-[C]methylated derivatives of the clinically used neprilysin inhibitor (NEPi) sacubitril ([C]SacOMe, (2R,4S)-ethyl 5-([biphenyl]-4-yl)-4-(4-[C]methoxy-4-oxobutanamido)-2-methylpentanoate) and LBQ657 ([C]MeOLBQ, (2R,4S)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid [C]methyl ester and [C]LBQOMe, (2R,4S)-5-(biphenyl-4-yl)-4-[(4-[C]methoxy-4-oxobutanamido)]-2-methylpentanoic acid) were evaluated to determine their potential as PET imaging tracers and investigate the effect of such labeling esterification on neprilysin (NEP) binding.
Methods: [C]MeOLBQ, [C]SacOMe and [C]LBQOMe were synthesized by O-[C]methylation using [C]methyl triflate. Binding of these radiolabeled derivatives (5 nM) were assessed by autoradiography on rat neprilysin rich kidney slices with or without 10 μM NEPi (thiorphan or sacubitril) for 20 min at 37 °C.
Structure-Guided Design of Substituted Biphenyl Butanoic Acid Derivatives as Neprilysin Inhibitors.
ACS Med Chem Lett
February 2020
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
Inhibition of neprilysin (NEP) is widely studied as a therapeutic target for the treatment of hypertension, heart failure, and kidney disease. Sacubitril/valsartan (LCZ696) is a drug approved to reduce the risk of cardiovascular death in heart failure patients with reduced ejection fraction. LBQ657 is the active metabolite of sacubitril and an inhibitor of NEP.
View Article and Find Full Text PDFRadiosynthesis of the C-methyl derivative of LBQ657 for PET investigation of the neprilysin inhibitor sacubitril.
J Labelled Comp Radiopharm
February 2020
Laboratoire de Radiochimie et Cyclotron, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
Neprilysin, also known as neutral endopeptidase, is a cell surface membrane metalo-endopeptidase that cleaves various peptides. Altered neprilysin expression has been correlated with various cancers and cardiovascular diseases. In this work, we present the radiosynthesis of the novel O- C-methylated derivative of LBQ657 (a potent neprilysin inhibitor).
View Article and Find Full Text PDFIn vitro and clinical evaluation of OATP-mediated drug interaction potential of sacubitril/valsartan (LCZ696).
J Clin Pharm Ther
August 2016
Translational Medicine, Drug Metabolism and Pharmacokintinetics, NIBR, East Hanover, NJ, USA.
What Is Known And Objective: Sacubitril/valsartan (LCZ696) has been recently approved for the treatment of heart failure (HF) patients with reduced ejection fraction. Several HF patients receive statins as co-medication.
Methods: Because clearance of statins is meditated via OATP1B1/1B3, the inhibition potential of these transporters by LCZ696 analytes was evaluated in vitro.
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