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-(11) C-methylated derivative of LBQ657 (a potent neprilysin inhibitor). (2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid [(11) C]methyl ester ([(11) C]MeOLBQ) is an analog of sacubitril where the alkyl ester is a (11) C-methyl instead of an ethyl. [(11) C]MeOLBQ was produced in a one-pot two-step synthesis. The O-(11) C-methylation of the pentanoic acid part was done with [(11) C]methyl triflate followed by the deprotection of the tert-butyl ester precursor in acidic conditions. [(11) C]MeOLBQ ([(11) C]7) was produced in 9.5 +/- 2.5% RCY (25 +/- 6% decay-corrected from [(11) C]CO2 , n = 3) high molar activity 348 +/- 100 GBq/mumol (9425 +/- 2720 mCi/mumol) 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.