Abstract
450
Objectives: The norepinephrine transporter (NET) has been linked to many psychiatric and neurological disorders, so PET imaging of the NET pathway is greatly desired. We developed the C-fluoropropyl nisoxetine analog (R)-N-methyl-3-(18F-3’-fluoropropyl)phenoxy)-3-phenylpropanamine(18F-MFP3). Here we report its synthesis and evaluation as a NET imaging agent. Methods: Radiosynthesis of 18F-MFP3 occurred as a 2 step process: F-18 was integrated into (R)-N-tert-butyloxycarbonyl-N-methyl-3-(3’-tosyloxypropyl)phenoxy)-3-phenylpropanamine, followed by deprotection of the N-BOC-protected amine group. 18F-MFP3 (0.2-0.3 mCi) was injected into control and nisoxetine (10 mg/kg) treated male Sprague-Dawley rats. The rhesus monkey anesthetized with ketamine (10 mg/kg) and xylazine (0.5 mg/kg), maintained on 1-1.5% isoflurane was studied on a ECAT EXACT HR+ PET scanner. The dynamic sequence of scans was attained 180 min post administration of ~4 mCi of 18F- MFP3 (2 Ci/μmol). PET images coregistered with MRI image template of the rhesus monkey provided anatomical detail. Results: 18F-MFP3 was obtained in 15% yield in 2.5 h. 18F-MFP3 binding in rat brain slices in vitro and ex vivo was consistent with known NET brain distribution. Radioactivity levels in ex vivo studies (2 h) in decreasing order were: locus coeruleus (LC) > thalamus (TH) > hippocampus (HP) > cortex (CTX) > striatum (ST) > cerebellum (CB) (LC/CB=2.1; TH/CB=1.7; HP/CB=1.6; ST/CB=1.3). PET-MRI images demonstrated significant binding in the TH, known to contain a high degree of NET sites. Uptake of 18F-MFP3 reached levels >0.013% injected dose/mL. Uptake in various brain regions including the TH peaked about 1 h post-injection, TH/CB=1.4. Cortical regions also showed significant binding. No 18F-MFP3 skull uptake was seen, suggesting little defluorination of the radiotracer occurred. Conclusions: High NET density is found in the TH, HP and especially LC (from where the NET pathway projects). 18F-MFP3 in vivo uptake revealed consistency with NET brain distribution. Although we expected the LC to have high NET binding, PET scanner resolution may have limited its detection. We demonstrated that 18F-MFP3 is a useful PET imaging agent for measuring NE uptake sites in the primate brain.
- Society of Nuclear Medicine, Inc.