Figure 1.
Two small molecule aryl fluorides chosen for radiofluorination and non-human primate PET imaging presented here.
Figure 2.
New electrophilic fluorination reagent.
Synthesis of high-valent palladium complex 7 that is an electrophilic fluorination reagent derived from complex 6 through fluoride capture.
Figure 3.
Two-step procedure for synthesis of radiolabeled aryl fluorides.
The procedure consists of capture of [18F]fluoride by palladium(IV) complex 6 to form electrophilic 18F-fluorination reagent [18F]-7 and fluorine transfer to aryl metal complexes.
Figure 4.
General palladium-mediated synthesis of radiolabeled aryl fluorides.
C–F bond formation is proposed to occur by oxidation of 9 with [18F]-7 leading to a proposed Pd(IV)–18F intermediate followed by C–F reductive elimination.
Figure 5.
Synthesis of palladium(II) aryl substrate 15.
Figure 6.
Synthesis of palladium(II) aryl substrate 20.
Figure 7.
Synthesis of aryl fluorides 1 and 2 via late-stage fluorination with electrophilic reagent 7.
Figure 8.
Palladium-mediated synthesis of [18F]-1 and [18F]-2 using [18F]-7 derived from [18F]fluoride.
(A) Synthesis of the electrophilic fluorination reagent [18F]-7 for reaction with palladium aryl complexes. (B) Synthesis of SSRI [18F]-1 on a scale suitable for NHP PET imaging. (C) Synthesis of 5-HT2C agonist [18F]-2 on a scale suitable for NHP PET imaging.
Figure 9.
Distribution and pharmacokinetic profile of [18F]paroxetine ([18F]-1) from MR-PET imaging in non-human primates.
(A) Summed images from 5–50 min of the dynamic PET collected following injection of [18F]-1. The images are fused with a structural (T1 weighted) MR image. Although [18F]-1 is a potent and selective ligand for the serotonin transporter (SERT), the observed binding does not match the distribution of SERT. This is indicative of high non-specific binding. The images highlight the overall high blood-brain-barrier penetration of [18F]-1 and heterogeneity of binding observed. (B) Whole-brain average time-activity curves from [18F]-1 from baseline and pretreatment (citalopram) studies.
Figure 10.
Preliminary [18F]-2 MR-PET imaging in non-human primates.
(A) Summed images from 5-50 min of the dynamic PET collected following two studies (baseline and ritanserin pretreated) with [18F]-2. The images highlight the overall high blood-brain-barrier penetration of [18F]-2 and heterogeneity of binding observed. The highest concentrations were noted in the thalamus, cerebellum, and occipital cortex. (B) Time-activity curves from region-of-interest (ROI) analysis from the dynamic data represented in A. As seen in the kinetic profiles, ritanserin did not fully block the uptake of [18F]-2; however it did reduce binding and alter the pharmacokinetic profile in the thalamus and cortex but not the cerebellum. The extent to which this represents 5HT2c binding will require validation by additional imaging experiments.