[ 11 C]NS9531, [ 11 C]NS9762 and [ 11 C]NS6417, specific SERT tracers: pre-clinical evaluation in pigs and optimization of synthesis conditions using [ 11 C]methyl triflate

Abstract Introduction NS9531, NS9762 and NS6417 are nitroquinolinyl-diazabicyclo-alkane derivatives that have been developed as inhibitors of serotonin reuptake transporters (SERT) by NeuroSearch A/S. Methods IC50 was measured on the up-take of serotonin, dopamine and noradrenaline in synaptosomes prepared from selected rat brain regions. For the pre-clinical evaluation in pigs, [ 11 C]NS9531, [ 11 C]NS9762 and [ 11 C]NS6417 were prepared by N -methylation using [ 11 C]methyl iodide. These syntheses were later on optimized regarding: 1) choice of labelled precursor; 2) HPLC purification conditions; and 3) formulation using SPE columns. The synthesis protocols were then fully automated on a GE FX c Pro. Preclinical evaluation was performed by PET studies in landrace pigs before and after treatment with citalopram. Results IC50 measurements showed that all three compounds have low nanomolar affinity for SERT, and micromolar affinity for DAT and NET. The radiochemical yield (r.y.) of all three ligands from [ 11 C]methyl iodide was higher than 30%. From [ 11 C]methyl triflate, the r.y. of [ 11 C]NS9531 and [ 11 C]NS9762 were higher than 80% whereas the r.y. of [ 11 C]NS6417 was 65%. Residual precursor amounts in final products could be significantly reduced by the use of [ 11 C]methyl triflate, Conclusion The three 11 C labelled PET tracers could be prepared in medium to high yield and high purity. IC50 measurements showed that the three NS compounds were highly selective, high affinity SERT inhibitors. PET studies in pig showed high brain uptake that could be blocked by citalopram pre-treatment.