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PET Imaging of A4b2* Nicotinic Acetylcholine Receptors: Qualitative Analysis of 18F-Nifene Kinetics in the Nonhuman Primate

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PET Imaging of A4b2* Nicotinic Acetylcholine Receptors: Qualitative Analysis of 18F-Nifene Kinetics in the Nonhuman Primate Journal of Nuclear Medicine, published on July 31, 2012 as doi:10.2967/jnumed.112.103846 PET Imaging of a4b2* Nicotinic Acetylcholine Receptors: Qualitative Analysis of 18F-Nifene Kinetics in the Nonhuman Primate Ansel T. Hillmer1,2, Dustin W. Wooten1,2, Maxim S. Slesarev2, Elizabeth O. Ahlers2, Todd E. Barnhart1, Dhanabalan Murali1,2, Mary L. Schneider3, Jogeshwar Mukherjee4, and Bradley T. Christian1,2,5 1Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin; 2Waisman Brain Imaging Laboratory, University of Wisconsin-Madison, Madison, Wisconsin; 3Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin; 4Department of Radiological Sciences, University of California-Irvine, Irvine, California; and 5Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin Key Words: nAChR; PET; nicotine; 18F-nifene; compartment The PET radioligand 2-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyr- modeling idine (18F-nifene) is an a4b2* nicotinic acetylcholine receptor J Nucl Med 2012; 53:1–10 (nAChR) agonist developed to provide accelerated in vivo equi- DOI: 10.2967/jnumed.112.103846 librium compared with existing a4b2* radioligands. The goal of this work was to analyze the in vivo kinetic properties of 18F- nifene with both kinetic modeling and graphical analysis tech- niques. Methods: Dynamic PET experiments were performed on 4 rhesus monkeys (female; age range, 9–13 y) using a small- animal PET scanner. Studies began with a high-specific-activity uch work in the last 15 y has been devoted toward 18 18 M F-nifene injection, followed by a coinjection of F-nifene and developing suitable PET radioligands to image a4b2* nico- unlabeled nifene at 60 min. Sampling of arterial blood with me- tinic acetylcholine receptors (nAChRs). These ligands bind tabolite analysis was performed throughout the experiment to b provide a parent radioligand input function. In vivo kinetics were with varying affinities to nAChRs containing either the 2or characterized with both a 1-tissue-compartment model (1TCM) a4 subunit, but most commonly to the a4b2 subtype, result- and a 2-tissue-compartment model, Logan graphical methods ing in the notation a4b2*. The impetus for developing these (both with and without blood sampling), and the multilinear ref- probes stems from the interest in this receptor system’s in- erence tissue model. Total distribution volumes and nondis- volvement in neurodevelopment, tobacco and alcohol addic- placeable binding potentials (BPND) were used to compare tion, and neuropathology. The disruption of cholinergic regional binding of 18F-nifene. Regions examined include the anteroventral thalamus, lateral geniculate body, frontal cortex, neurotransmission has been implicated in Alzheimer disease, subiculum, and cerebellum. Results: The rapid uptake and leading to the application of acetylcholinesterase inhibitors binding of 18F-nifene in nAChR-rich regions of the brain was as a treatment option for the symptoms of Alzheimer disease appropriately modeled using the 1TCM. No evidence for spe- (1,2). Evidence of declining nAChR densities has been asso- cific binding of 18F-nifene in the cerebellum was detected on the ciated with Alzheimer disease, Parkinson disease, and healthy basis of the coinjection studies, suggesting the suitability of the aging (3,4). Alterations from normal nAChR functioning cerebellum as a reference region. Total distribution volumes in 3 have been implicated in other neurodegenerative diseases, the cerebellum were 6.91 6 0.61 mL/cm .BPND values calcu- lated with the 1TCM were 1.60 6 0.17, 1.35 6 0.16, 0.26 6 including epilepsy (5), tobacco abuse (6), schizophrenia (7), 0.08, and 0.30 6 0.07 in the anteroventral thalamus, lateral and deficiencies in neurodevelopment, such as effects due to geniculate body, frontal cortex, and subiculum, respectively. fetal alcohol exposure (8). For all brain regions, there was a less than 0.04 absolute differ- 11C-nicotine was the first radioligand developed for target- ence in the average BPND values calculated with each of the ing a4b2* nAChR binding; however, it was found to have 1TCM, multilinear reference tissue model, and Logan methods. high nonspecific binding and rapid dissociation, rendering Conclusion: The fast kinetic properties and specific regional 18 18 it unsuitable for PET studies (9). The radioligand 2- F- binding of F-nifene promote extension of the radioligand into 18 preclinical animal models and human subjects. FA-85380 (2- F-FA) has been used the most extensively for PET studies of a4b2* nAChRs (10,11). Because of its 18 Received Feb. 2, 2012; revision accepted Apr. 30, 2012. slow in vivo behavior, PET experiments using 2- F-FA re- For correspondence or reprints contact: Ansel T. Hillmer, Department of quire more than 5 h of imaging for accurate measurement Medical Physics, University of Wisconsin-Madison, 1111 Highland Ave., a b Madison, WI 53705. of 4 2* nAChR binding throughout all regions of the brain E-mail: [email protected] (12). Applications of this radioligand for PET studies have Published online nnnn. COPYRIGHT ª 2012 by the Society of Nuclear Medicine and Molecular included studies of healthy aging (13), Alzheimer disease Imaging, Inc. (14), Parkinson disease (15), and epilepsy (16). ANALYSIS OF 18F-NIFENE KINETICS • Hillmer et al. 1 jnm103846-pm n 7/31/12 Copyright 2012 by Society of Nuclear Medicine. The prolonged scanning procedures required for 2-18F-FA 10 min. The mixture was then extracted with 4 mL of methylene quantification has spurred the development of various new chloride and passed through a neutral alumina Sep-Pak (Waters). a4b2* nAChR radioligands with faster kinetic properties, The methylene chloride was dried and the product purified with including both agonists and antagonists (17). Agonist radio- HPLC. The use of a new separation method—consisting of m · ligands, in particular, are of great interest because other re- a C-18 Prodigy column (10 m, 250 10 mm; Phenomenex) with a mobile phase of 55% 0.05 M sodium acetate, 27% methanol, and ceptor systems, including the dopamine and serotonin 18% tetrahydrofuran at a flow rate of 8.0 mL/min—was incorpo- systems, have found agonist radioligands to exhibit increased rated into the 18F-nifene purification. This HPLC method was pre- sensitivity to competing endogenous neurotransmitter levels viously developed for the synthesis of 18F-MPPF, a serotonin (18,19). This feature of nAChR radioligands will prove vital 5-hydroxytryptamine subtype 1A radioligand whose precursor in evaluating acetylcholinesterase inhibitors for applications also contains a nitro-leaving group (23). Retention time of the with Alzheimer disease. The a4b2* agonist radioligand N-Boc-18F-nifene was approximately 14 min. The collected 2-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (18F-nifene) eluate (;5mL)wasthendilutedin50mLofwater,trapped was developed with the aim of improving on the success of on a C-18 Sep-Pak (Waters), and eluted with 1 mL of acetoni- 2-18F-FA by creating an analog with faster kinetic properties trile. Deprotection was performed with the addition of 200 mL ° and a similar binding profile (20). Previous studies have of 6 N HCl, followed by heating at 80 C for 10 min. The mixture shown that 18F-nifene exhibits fast transient equilibrium times was then dried and pH adjusted to 7.0 with sodium bicarbonate. Ethanol (0.5 mL) and sterile saline were added for a total volume of approximately 30 min, resulting in scanning procedures of of 10 mL. This final product was purified with a preconditioned C-18 18 a b less than an hour. Elevated F-nifene binding in 4 2* Sep-Pak (Waters) to remove any residual intermediate species (i.e., nAChR-rich regions of the brain was also observed, with remaining Boc-protected product), followed by sterile filtration with target-to-background binding levels suitable for applications a0.22-mm Millipore filter for final formulation. in preclinical research (21). These studies preliminarily dem- onstrated the viability of 18F-nifene PET experiments for Subjects translation into human subjects. PET scans with 18F-nifene were acquired for 4 Macaca mulatta The goal of the present work was to extend previous (rhesus monkey) subjects (4 females; weight range, 6.6–11.9 kg). studies with 18F-nifene by examining its behavior in arterial All housing and experimental procedures obeyed institutional blood to obtain quantitative measures of a4b2* nAChR guidelines and were approved by the institutional animal care binding with both model-based and graphical analysis tech- and use committee. Subjects were anesthetized before PET niques. The anteroventral thalamus and lateral geniculate procedures with ketamine (10 mg/kg intramuscularly) and main- tained on 1%–1.5% isoflurane for the duration of the experiment. body were analyzed because of their high binding levels Atropine sulfate (0.27 mg intramuscularly) was administered and their role in a variety of neurodegenerative deficits, to minimize secretions. Body temperature, breathing rate, heart while the subiculum and frontal cortex were also examined rate, and blood oxygen saturation levels were recorded for the as targets because of alterations in binding associated with duration of the experiment. The radiotracer was administered Alzheimer disease and tobacco addiction (2,22). Blocking via bolus injection in the saphenous vein, and arterial blood sam- studies with unlabeled nifene were performed to evaluate ples were withdrawn from the tibial artery in the opposing limb. the viability of the cerebellum to serve as a region of neg- After completion of the experiment, the subject was returned to ligible detectable specific binding for techniques using ref- its cage and monitored until fully alert. erence region graphical analysis. These studies provide a necessary step toward validating the use of 18F-nifene Data Acquisition for studying the nAChR system during neurodevelopment A Concorde microPET P4 scanner was used for the acquisition of PET data. This scanner has an axial field of view of 7.8 cm, and in disease-specific models.
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