Radiosynthesis of the 11C‐methyl derivative of LBQ657 for PET investigation of the neprilysin inhibitor sacubitril.

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‐11C‐methylated derivative of LBQ657 (a potent neprilysin inhibitor). (2R,4S)‐5‐(Biphenyl‐4‐yl)‐4‐[(3‐carboxypropionyl)amino]‐2‐methylpentanoic acid [11C]methyl ester ([11C]MeOLBQ) is an analog of sacubitril where the alkyl ester is a 11C‐methyl instead of an ethyl. [11C]MeOLBQ was produced in a one‐pot two‐step synthesis. The O‐11C‐methylation of the pentanoic acid part was done with [11C]methyl triflate followed by the deprotection of the tert‐butyl ester precursor in acidic conditions. [11C]MeOLBQ ([11C]7) was produced in 9.5 ± 2.5% RCY (25 ± 6% decay‐corrected from [11C]CO2, 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. [ABSTRACT FROM AUTHOR]