RT Journal Article
SR Electronic
T1 Radiosynthesis and characterization in non-human primates of three enantiomerically pure PET radioligands for imaging the GluN2B subunit of the NMDA receptor complex
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 265
OP 265
VO 61
IS supplement 1
A1 MingQiang Zheng
A1 Hazem Ahmed
A1 Kelly Smart
A1 Yuping Xu
A1 Daniel Holden
A1 Michael Kapinos
A1 Zachary Felchner
A1 Jim Ropchan
A1 Gilles Tamagnan
A1 Richard Carson
A1 Yiyun Huang
A1 Simon Ametamey
YR 2020
UL http://jnm.snmjournals.org/content/61/supplement_1/265.abstract
AB 265Objectives: The NMDA receptors are involved in diseases of the central nervous system including Alzheimer’s disease, ischemic brain injury, and schizophrenia. We have previously reported the evaluation of the novel radioligands 11C- and 18F-OF-Me-NB1 and demonstrated their in vivo binding specificity to GluN2B-containing NMDA receptor in rodents [1]. Here we report their evaluation in rhesus monkeys. Methods: Enantiopure (R)-11C-OF-Me-NB1 was synthesized by O-methylation with 11C-MeI. (R)- and (S)-18F-OF-Me-NB1 were prepared by 18F-fluorination of the enantiomerically pure boronic ester precursors followed by cleavage of the ester protecting group with NaOH. PET scans of up to 180 min each in rhesus monkeys were conducted on the Focus 220 scanner. Plasma metabolite analysis was performed by HPLC and the arterial input function was calculated. Regional brain time-activity curves (TACs) were generated and analyzed with one-tissue (1TC) and two-tissue (2TC) compartment models and multilinear analysis-1 (MA1) method to obtain regional volumes of distribution (VT, mL/cm3). Results: All target compounds were obtained in >95% radiochemical and enantiomeric purity, with molar activity of 14±5 mCi/nmol for 11C-OF-Me-NB1 (n=3) and 3.5±1.2 mCi/nmol for 18F-OF-Me-NB1 (n=5) at the end of the synthesis. Metabolism was fast with ~30% parent compound for (R)-11C-OF-Me-NB1 and (R)-18F-OF-Me-NB1 at 30 min after injection, and ~18% for (S)-18F-OF-Me-NB1. Plasma free fraction for all three forms of the radiotracer was ~2%. In the monkey brain both (R)-11C-OF-Me-NB1 and (R)-18F-OF-Me-NB1 displayed very similar pattern of fast uptake and clearance, while (S)-18F-OF-Me-NB1 showed lower brain uptake and faster clearance in all brain regions. Radioactivity uptake was high in the putamen, hippocampus and thalamus, medium in the occipital cortex and cerebellum, and low in the white matter (centrum semiovale). Both the 1TC model and MA1 method fitted the TACs well and provided reliable VT estimates, ranging from 8.2 in the centrum semiovale to 13.9 in the cingulate cortex for (R)-11C- and (R)-18F-OF-Me-NB1, compared to 10.8 in the occipital cortex to 15.6 in the cingulate cortex for (S)-18F-OF-Me-NB1. Conclusions: We have successfully synthesized and evaluated three enantiomerically pure radioligands for targeting the GluN2B subunit of the NMDA receptor complex. Blocking studies are currently underway to define the binding specificity of these radiotracers in non-human primates and to assess their potential for clinical translation. Research supports: 1. Swiss National Science Foundation; 2. NIH grant U01MH107803. References: 1. Haider A et al. J Nucl med 2019; 60:1167