RT Journal Article
SR Electronic
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
FD Society of Nuclear Medicine
SP 259
OP 266
DO 10.2967/jnumed.118.212134
VO 60
IS 2
A1 Haider, Achi
A1 Iten, Irina
A1 Ahmed, Hazem
A1 Herde, Adrienne Müller
A1 Gruber, Stefan
A1 Krämer, Stefanie D.
A1 Keller, Claudia
A1 Schibli, Roger
A1 Wünsch, Bernhard
A1 Mu, Linjing
A1 Ametamey, Simon M.
YR 2019
UL http://jnm.snmjournals.org/content/60/2/259.abstract
AB 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.