HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JNM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chattopadhyay, S. Articles by Mukherjee, J. Search for Related Content PubMed PubMed Citation Articles by Chattopadhyay, S. Articles by Mukherjee, J.

Synthesis and Evaluation of Nicotine ₄ß₂ Receptor Radioligand, 5-(3'-¹⁸F-Fluoropropyl)-3-(2-(S)-Pyrrolidinylmethoxy)Pyridine, in Rodents and PET in Nonhuman Primate

¹ Department of Psychiatry and Human Behavior. Brain Imaging Center, University of California, Irvine, California
² Department of Pharmacology, University of California, Irvine, California
³ Department of PET/Nuclear Medicine, Kettering Medical Center, Dayton, Ohio

View larger version (21K): [in a new window]   FIGURE 1. Chemical structures of 4ß2 radioligands. (A) Epibatidine analogs. (B) Pyridylether analogs. (C) Azetidinylether analogs in human studies. (D) Fluoroalkyl dervatives of pyrrolinylethers (nifrolidine, this work).

View larger version (19K): [in a new window]   FIGURE 2. Synthesis scheme for 5-(3'-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine (9, nifrolidine) and tosylate precursor, 5-(3'-[[4-methylphenyl]sulfonyloxy]propyl)-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine 10 for radiolabeling with 18F. BOC = butoxycarbonyl.

View larger version (45K): [in a new window]   FIGURE 3. Inhibition of 125I-IEB in rat brain slices by nifrolidine. (A) Binding of 125I-IEB without nifrolidine and cytisine in cortex (Ctx), hippocampus (Hpx), medial habenula (MHb), dorsolateral geniculate (DLG), ventral posteriomedial nucleus of thalamus (VPM), and optic tract (opt). (B) Binding of 125I-IEB with 200 nmol/L cytisine. (C) Binding of 125I-IEB in presence of 30 nmol/L nifrolidine. (D) Binding of 125I-IEB in presence of 30 nmol/L nifrolidine and 200 nmol/L cytisine. (E) Binding of 125I-IEB without nifrolidine and cytisine in pineal (Pin), superior colliculus (SuG), central gray, and interpeduncular nucleus (IPn). (F) Binding of 125I-IEB with 200 nmol/L cytisine. (G) Binding of 125I-IEB in presence of 30 nmol/L nifrolidine. (H) Binding of 125I-IEB in presence of 30 nmol/L nifrolidine and 200 nmol/L cytisine. (I) Plot shows percent inhibition of 125I-IEB by nifrolidine at 4ß2, 3ß2, and 3ß4 receptor subtypes obtained from autoradiographic experiments.

View larger version (29K): [in a new window]   FIGURE 4. (A) Reaction scheme shows radiosynthesis of 18F-N-BOC-nifrolidine and HPLC purification of 18F-N-BOC-nifrolidine using C18 reverse-phase semipreparative column eluted with 60% acetonitrile/0.1 mol/L ammonium formate at flow rate of 4.0 mL/min. Retention time of 18F-N-BOC-nifrolidine was 11.5 min. (B) Reaction scheme shows radiosynthesis of 18F-nifrolidine and HPLC purification of 18F-nifrolidine using C18 reverse-phase semipreparative column eluted with gradient of 0.1 mol/L ammonium formate (100%)/acetonitrile (0%) at time 1 min to 0.1 mol/L ammonium formate (40%)/acetonitrile (60%) at time 35 min with flow rate of 4.0 mL/min. Retention time of 18F-nifrolidine was 22 min. UV = ultraviolet.

View larger version (77K): [in a new window]   FIGURE 5. In vitro autoradiographic studies of 18F-nifrolidine in rat brain slices. (A) Binding of 18F-nifrolidine in 20-µm coronal slices (74 kBq/mL, 25°C; HP = hippocampus). (B) Total binding of 18F-nifrolidine in 10-µm horizontal slices (37 kBq/mL, 25°C) and binding in presence of 10 µmol/L nicotine. FC = frontal cortex; ST = striata; AV = anteroventral thalamic nucleus; TH = thalamus; PS = postsubiculum; CB = cerebellum). (C) Plot shows amount of 18F-nifrolidine binding (DLU/mm2) in brain regions shown in Figure 5B.

View larger version (72K): [in a new window]   FIGURE 6. (A) MRI brain slice templates of rhesus monkey brain (axial, coronal, and sagittal sections) show putamen (Pu), thalamus (Th), occipital cortex (OC), temporal cortex (TC), frontal cortex (FC), cerebellum (Cb), and brain stem (BS). (B) Corresponding PET image slices acquired using 18F-nifrolidine. Images are shown in hot-metal color scale, where white indicates highest amount of radiotracer activity. (C) Distribution of 18F-nifrolidine in rhesus monkey brain. Summed PET images (100–150 min) show binding of 18F-nifrolidine in select brain slices. Brain regions include cingulate gyrus (CG), FC, anterioventral thalamus (AVT), insular cortex (IC), caudate (Cd), anteriomedial thalamus (AMT), ventrolateral thalamus (VLT), occipital cortex (OC), lateral geniculate (LG), temporal cortex (TC), and cerebellum (Cb).

View larger version (25K): [in a new window]   FIGURE 7. (A) Time–activity curves of 18F-nifrolidine binding in select areas of monkey brain corresponding to regions identified in Figure 6C (AMT, VLT, TC, OC, LG, and Cb). (B) Ratio plot of brain regions (in A) to Cb.