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18F-Niofene) As a Potential Imaging Agent for Nicotinic Α4β2 Receptors

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18F-Niofene) As a Potential Imaging Agent for Nicotinic Α4β2 Receptors Am J Nucl Med Mol Imaging 2014;4(4):354-364 www.ajnmmi.us /ISSN:2160-8407/ajnmmi0000467 Original Article Synthesis and evaluation of 2-18F-fluoro-5-iodo-3- [2-(S)-3,4-dehydropyrrolinylmethoxy]pyridine (18F-Niofene) as a potential imaging agent for nicotinic α4β2 receptors Sharon A Kuruvilla1, Ansel T Hillmer2, Dustin W Wooten2, Ashna Patel1, Bradley T Christian2, Jogeshwar Mukherjee1 1Preclinical Imaging, Department of Radiological Sciences, University of California, Irvine, CA 92697, USA; 2De- partment of Medical Physics, University of Wisconsin, Madison, WI 53705, USA Received April 8, 2014; Accepted April 22, 2014; Epub June 7, 2014; Published June 15, 2014 Abstract: Nicotinic α4β2 acetylcholine receptors (nAChRs) have been implicated in various pathophysiologies in- cluding neurodegenerative diseases. Currently, 2-18F-A85380 (2-FA) and 5-123I-A85380 (5-IA) are used separately in human PET and SPECT studies respectively and require >4-6 hours of scanning. We have developed 2-fluoro-5-iodo- 3-[2-(S)-3-dehydropyrrolinylmethoxy]pyridine (niofene) as a potential PET/SPECT imaging agent for nAChRs with an aim to have rapid binding kinetics similar to that of 18F-nifene used in PET studies. Niofene exhibited a 10-fold better in vitro binding affinity in rat brain than that of nicotine. The relative binding of niofene was similar to that of niodene and twice as better as that of nifene. In vitro autoradiography in rat brain slices alongside niodene indicated selec- tive binding of niofene to regions consistent with α4β2 receptor distribution. Niofene, 10 nM, displaced >70% of 3H-cytisine bound to α4β2 receptors in rat brain slices. Radiolabeling of 18F-niofene was achieved in 10-15% radio- chemical yield in high specific activities >2 Ci/μmol and showed rapid in vivo kinetics similar to that of 18F-nifene and 18F-nifrolene. In vivo PET in rats showed rapid uptake in the brain and selective localization in receptor regions such as the thalamus (TH). Pseudoequilibrium with 18F-niofene was achieved in 30-40 minutes, which is similar to that of 18F-nifene. Further evaluation of 18F-niofene as a potential PET imaging agent is underway. Future studies will be conducted to radiolabel niofene with iodine-123 for use in SPECT imaging. Keywords: Nicotine, nifene, niodene, nifrolene, fluorine-18 Introduction We have developed several α4β2 imaging agents in our laboratory of which the leading Alterations of α4β2 nicotinic acetylcholine ones are the following: agonist 18F-nifene (for receptors (nAChRs) in the brain have shown PET) and putative antagonists 123I-niodene (for some significance in the etiology of neurode- SPECT) and 18F-nifrolene (for PET). With a generative diseases such as Alzheimer’s dis- 3,4-dehydroproline ring system, 18F-nifene has ease (AD) and Parkinson’s disease. More shown rapid brain imaging kinetics with a recently, this receptor has been found to be reduced scan time of <1 hour, which is faster overexpressed in mice models of lung tumors than the well-known 2-FA [6]. 123I-Niodene [1]. Efforts on imaging α4β2 receptors using exhibits similar binding behavior as that of positron emission tomography (PET) and sin- nifene, such as its high affinity for α4β2 recep- gle-photon emission computed tomography tors, and it also incorporates a 3,4-dehydropro- (SPECT) are currently underway with 2-18F- line ring system in its structure. This is evident A85380 (2-FA) and 5-123I-A85380 (5-IA) used in when niodene displaces specifically bound human studies for PET and SPECT respectively 18F-nifene in rat brain slices at low concentra- [2-5]. Although successful, 2-FA and 5-IA both tions [7]. 18F-Nifrolene also has a 3,4-dehydrop- require a period >4-6 hours to work, which is roline ring system that allows it to have rapid not ideal for patient comfort. binding kinetics similar to that of 18F-nifene. All Niofene PET Scientific. S( )-tert-butyl 2-(hydroxy- methyl)-2,5-dihydro-1H-pyrrole-1 -carboxylate was purchased from Aroma Circle (San Diego, CA, USA) and 2-Bromo-5-iodopyridin-3-ol was purchased from Sigma-Aldrich (St. Louis, MO, USA). 3H-Cytisine (32.7 Ci/mmol specific activity) was purchased from Perkin Elmer Life and Analytical Sciences (Boston, MA, USA). All water was deionized to specific resistance of <18 mΩ cm using a Millipore Milli-Q water purification system. Electrospray mass spectra were obtained on a Model 7250 mass spectrometer (Micromass LCT). Proton NMR spectra were recorded on a Bruker OMEGA 500-MHz Figure 1. Chemical structures of α4β2 nAChRs binding agents. Nico- spectrometer. Analytical thin layer tine 1; Nifene 2; Niodene 3; Nifrolene 4; Niofene 5. chromatography (TLC) was carried out on silica-coated plates (Baker- three agents express high in vitro binding affin- Flex, Phillipsburg, NJ, USA). Chromatographic ity for α4β2 receptors in rat brain homogenate separations were carried out on preparative 3 using H-cytisine, with nifene’s Ki = 0.50 nM, TLC (silica gel GF 20_20 cm, 2000 Am thick; niodene’s Ki = 0.27 nM, and nifrolene’s Ki = Alltech Assoc., Deerfield, IL, USA) or semi-pre- 0.36 nM [8]. parative reverse-phase columns using the Gilson high-performance liquid chromatogra- Due to the promising characteristics of nifene phy (HPLC) systems. Tritium was assayed by and niodene, we have decided to combine their using a Packard Tri-Carb Liquid scintillation molecular structures to develop a hybrid mole- counter with 65% efficiency. High specific activ- cule, 2-fluoro-5-iodo-3-[2-(S)-3-dehydropyrroli- 18 nylmethoxy]pyridine (niofene) as a potential ity F-fluoride was produced in the MC-17 PET/SPECT imaging agent for nAChRs (Figure cyclotron or the GE cyclotron using oxygen-18 18 18 1). Our goal with incorporating the 3,4-dehydro- enriched water ( O to F using p, n reaction). 18 proline ring is to have niofene exhibit similar The high specific activity F-fluoride was used rapid kinetics to that of nifene. The presence of in subsequent reactions which were carried out the iodine at the 5-position causes niofene to in automated radiosynthesis units [either a become more of an antagonist and share simi- chemistry processing control unit (CPCU) or a lar binding characteristics as nifrolene. nuclear interface fluorine-18 module]. Flu- Furthermore, the addition of both fluorine and orine-18 radioactivity was counted in a Capintec iodine is to allow niofene to be used in either dose calibrator, whereas low-level counting was PET or SPECT imaging, depending on the user’s carried out in a well counter (Cobra quantum, preference in imaging modalities. Packard Instruments, Boston, MA, USA). Rat brain slices were obtained on a Leica 1850 We report here the synthesis of niofene, in vitro cryotome. Tritiated cytisine autoradiographic binding affinity in rat brain homogenate,in vitro studies were carried out by exposing tissue autoradiographic studies in rat brain slices, samples on storage phosphor screens. The radiosynthesis of 18F-niofene, and in vivo PET apposed phosphor screens were read and ana- imaging studies in rat. lyzed by the OptiQuant acquisition and analysis Materials and methods program of the Cyclone Storage Phosphor System (Packard Instruments). All animal stud- General ies were approved by the Institutional Animal Care and Use Committee of University of All chemicals and solvents were of analytical or California-Irvine and University of Wisconsin- HPLC grade from Sigma-Aldrich and Fisher Madison, Madison, WI. 355 Am J Nucl Med Mol Imaging 2014;4(4):354-364 Niofene PET Figure 2. Synthesis for 18/19F-niofene 10a and 10b. Diisopropyl azodicarboxylate (DIAD) was added to a solution of 6, 7, and triphenylphosphine (Ph3P) in tetrahydrofuran (THF) that was stirred and cooled at 0°C . The reaction mixture came to room temperature over a period of 2 hours and was stirred overnight. Bromo-intermediate 8 served as a precursor for fluorination using tetrabutylammonium fluoride (TBAF) and radiofluorination using18 F-fluoride, Krypto- fix and potassium carbonate (K2CO3) in dimethylsulfoxide (DMSO)-acetonitrile (CH3CN). Deprotection of 9a and 9b was carried out using trifluoroacetic acid (TFA) in dichloromethane (DCM) to yield niofene, 10a or 18F-niofene 10b. Chemistry 2-fluoro-5-iodo-3-[2-(S)-3-dehydropyrrolinylme- thoxy]pyridine (10a Niofene): In order to pre- 3-[2-(S)-N-tertbutoxycarbonyl-2-pyrrolinemetho- pare 9a, two fluorination methods were carried xy]-2-bromo-5-iodopyridine (8): Niofene precur- out as described below under methods A and sor 8 was produced under Mitsunobu conditio- B. ns as previously reported (Figure 2) [7]. Di- isopropyl azodicarboxylate (DIAD; 0.2 mL) was Method A: 3-[2-(S)-N-tertbutoxycarbonyl-2-pyr- added to a solution of 2-bromo-5-iodopyridin- rolinemethoxy]-2-bromo-5-iodopyridine, 8 (46 3-ol (0.16 g, 0.55 mmol), (S)-tert-butyl 2- mg; 0.095 mmol) was taken in 2 mL of THF and (hydroxymethyl)-2,5-dihydro-1Hpyrrole-1-car- tetra-n-butylammonium fluoride (TBAF; 1 mL; 1 boxylate (0.1 g; 0.50 mmol) and triphenylphos- mmol) in a round-bottom flask. The mixture was phine (0.19 g) in tetrahydrofuran (THF; 10 mL), refluxed at 75-85°C for 24 hours. Solution was stirred under argon and cooled at 0°C. The purified by preparative TLC (9:1 dichlorometh- reaction mixture was allowed to come up to ane (DCM): MeOH). Product yield was 6.9 mg ambient temperature over a period of 2 hours (0.017 mmol; 18% yield). and was stirred overnight. The reaction mixture was evaporated to dryness and the residue Method B: 3-[2-(S)-N-tertbutoxycarbonyl-2-pyr- was purified by preparative TLC (1:4, EtOAc in rolinemethoxy]-2-bromo-5-iodopyridine, 8 (46 hexane) to give pure product 3-[2-(S)-N-ter- mg; 0.095 mmol) was dissolved in anhydrous tbutoxycarbonyl-2-pyrrolinemethoxy]-2-bromo- acetonitrile.
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