TY - JOUR T1 - Identification and Preclinical Evaluation of a Radiofluorinated Benzazepine Derivative for Imaging the GluN2B Subunit of the Ionotropic NMDA Receptor JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 259 LP - 266 DO - 10.2967/jnumed.118.212134 VL - 60 IS - 2 AU - Ahmed Haider AU - Irina Iten AU - Hazem Ahmed AU - Adrienne Müller Herde AU - Stefan Gruber AU - Stefanie D. Krämer AU - Claudia Keller AU - Roger Schibli AU - Bernhard Wünsch AU - Linjing Mu AU - Simon M. Ametamey Y1 - 2019/02/01 UR - http://jnm.snmjournals.org/content/60/2/259.abstract N2 - The previously reported 11C-labeled GluN2B PET radioligand 11C-Me-NB1 served as a starting point for derivatization and led to the successful development of a radiofluorinated analog designated (R)-18F-OF-Me-NB1. Given the short physical half-life of 20.3 min for 11C, (R)-18F-OF-Me-NB1 with a physical half-life of 109.8 min would allow satellite distribution to nuclear medicine facilities without an on-site cyclotron. Methods: Two fluorinated Me-NB1 derivatives, OF-Me-NB1 and PF-Me-NB1, were synthesized. On chiral resolution, the respective enantiomers were radiolabeled with 11C and assessed in a proof-of-concept study by applying in vitro autoradiography on rodent brain sections. On the basis of the autoradiograms, (R)-OF-Me-NB1 was selected for radiofluorination and preclinical evaluation by ex vivo autoradiography, PET imaging, biodistribution, and metabolite studies on Wistar rats. To rule out off-target binding to the σ1 receptor (σ1R), brain uptake of (R)-18F-OF-Me-NB1 in wild-type mice was compared with that in σ1R knock-out mice. Results: Autoradiographic assessment revealed that both enantiomers of 11C-PF-Me-NB1 distributed homogeneously across all brain regions on rodent brain sections. In contrast, the 2 enantiomers of 11C-OF-Me-NB1 exhibited an entirely different behavior. Although (S)-11C-OF-Me-NB1 bound to virtually all brain regions, with considerable σ1R binding, (R)-11C-OF-Me-NB1 exhibited high selectivity and specificity for the GluN2B-rich rat forebrain. These findings were confirmed for the radiofluorinated analog (R)-18F-OF-Me-NB1, which was obtained via copper-mediated radiofluorination in radiochemical yields of 13%–25% and molar activities ranging from 61 to 168 GBq/μmol. PET imaging and biodistribution studies on Wistar rats indicated an appropriate pharmacokinetic profile and high in vivo specific binding of (R)-18F-OF-Me-NB1 as revealed by blocking studies with the GluN2B antagonist CP101,606. Off-target binding to the σ1R was excluded by PET imaging of σ1R knock-out mice. Half-maximal receptor occupancy by CP101,606 occurred at 8.3 μmol/kg (intravenous). Conclusion: (R)-18F-OF-Me-NB1 is a promising radiofluorinated probe that exhibits specificity and selectivity for the GluN2B-containing N-methyl-d-aspartate complex and enables in vivo target occupancy studies on rodents. ER -