Synthesis, evaluation and metabolic studies of radiotracers containing a 4-(4-[18F]-fluorobenzyl)piperidin-1-yl moiety for the PET imaging of NR2B NMDA receptors.

Abstract In this study, novel specific PET radioligands containing the 4-(4-fluorobenzyl)piperidine moiety and selectively antagonistic for the NR2B subunit containing NMDA receptors were developed. Two antagonists, RGH-896 ( 1a ) and 4-(4-fluorobenzyl)piperidinyl-1-methyl-2-benzimidazol-5-ol ( 2a ), belonging to two different structural families, were radiolabeled by an aromatic nucleophilic radiofluorination followed by a reduction of the para-position carbonyl function. Radiotracers [ 18 F] 1a , [ 18 F] 2a or the pattern 4-(4-[ 18 F]-fluorobenzyl)piperidine ([ 18 F] 6 ) demonstrated an identical in vivo behavior with high accumulation of radioactivity in bone and cartilage which would suggest a radiodefluorination of the radiotracers. The identification of metabolites from 6 by LC-MS-MS confirmed the significant degree of defluorination as a result of the in vivo hydroxylation in the benzyl ring. In conclusion, [ 18 F] 1a or [ 18 F] 2a are not suitable for imaging the NR2B NMDA receptors due to their poor brain penetration. We also argue for a cautious use of the radiolabeled pattern, 4-(4-[ 18 F]-fluorobenzyl)piperidine, to develop PET radiotracers.