Browse > Article

Synthesis and Evaluation of $2-[^{18}F]Fluoro-A85380$, a Radioligand for ${\alpha}_4{\beta}_2$ Nicotinic Acetylcholine Receptor Imaging  

Ryu, Eun-Kyoung (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine)
Choe, Yearn-Seong (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine)
Kim, Sang-Eun (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine)
Hwang, Sae-Hwan (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine)
Paik, Jin-Young (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine)
Choi, Yong (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine)
Lee, Kyung-Han (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine)
Kim, Byung-Tae (Departments of Nuclear Medicine and Biomedical Engineering, Samsung Medical Center, Sungkyunkwan University School of Medicine)
Publication Information
The Korean Journal of Nuclear Medicine / v.36, no.4, 2002 , pp. 261-270 More about this Journal
Abstract
Purpose: Nicotinic acetylcholine receptors (nAChRs), which mediate excitatory neurotransmission, are known to participate in various neurophysiological functions. Severe losses of nAChRs have been noted in Alzheimer's and Parkinson's diseases. Therefore, noninvasive and quantitative imaging of nAChRs would offer a better understanding on the function of these receptors. In this study, $2-[^{18}F]fluoro-A85380\;([^{18}F]1)$, an ${\alpha}_4{\beta}_2$ nAChRs radioligand, was prepared using one HPLC purification and evaluated in mouse brain, and the results were compared with those in the literature. Materials and Methods: $[^{18}F]1$ was prepared by $[^{18}F]$fluorination of the iodo precursor followed by acidic deprotection and then purified by HPLC. Tissue distribution studies were performed in mouse brain at the indicated time points and the result was expressed as %ID/g. Inhibition studies were also carried out with pretreatment of various ligands. Results: One HPLC purification method gave the desired product in 15-20% radiochemical yield and with high specific activity ($38-55GBq/{\mu}mol$). Tissue distribution studies showed that $[^{18}F]1$ specifically labeled nAChRs in mouse brain with a high thalamus to cerebellum uptake ratio (13.8 at 90 min). Inhibition studios demonstrated selective binding of $[^{18}F]1$ to nAChRs, blocking the uptake of the $[^{18}F]1$ in nAChR-rich legions by selective ligands such as cytisine and nicotine which are well-known nAChRs agonists. Conclusion: This study demonstrated that the $[^{18}F]1$ produced by the method using one HPLC purification gave the results similar to those reported in the literature. Therefore, this synthetic method can be readily applied to the routine preparation of $[^{18}F]1$, a PET radioligand for ${\alpha}_4{\beta}_2$ nAChRs imaging.
Keywords
${\alpha}_4{\beta}_2$ nicotinic acetylcholine receptors; $2-[^{18}F]fluoro-A85380$; PET;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Levine ED, Ross JE. Acute and chronicnicotinic imteractions with dopamine systemsand working memory performance. Ann N YAcad Sci 1995;757:245-52.
2 Whitehouse PJ, Martino AM, Antuono PG,Lowenstein PR, Coyle JT, Price DL, et. al.Nicotinic acetylcholine binding sites in Alzheimer'sdisease. Brain Res 1986;371:146-51.
3 Nyback H, Nordberg A, Langstrom B, HalldinC, Ahlin A, Swahn CG, et al. Attempts tovisualize nicotinic receptors in the brain ofmonkey and man by positron emission tomography.Progr Brain Res 1989;79:313-9.
4 Horti AG, Scheffel V, Kims AS, Musachio JL,Ravert HT, mathews WB. et al. Synthesis andevaluation of [llq_N_ methylated analogs ofepibatidine as tracers for PET studies ofnicotinic acetylcholine receptors. J Med Chern1998;41:4199-206.
5 Koren AO, Horti AG, Mukhin AG, Gundisch D,Kimes AS, Dannals RF, et al. 2-, 5-, and6-Halo-3-(2(S)-azetidinylmethoxy) pyridines: Syn"thesis, affinity for nicotinic acetylcholinereceptors, and molecular modeling. J Med Chem1998;41:3690-8.
6 Sullivan JP, Donnelly-Roberts D, Briggs CA,Anderson DJ, Gopalakrishnan M, PlattoniKaplanM, et al. A-85380 [3-(2(S)-azetidinylmethoxy)pyridine]: In vitro pharmacologicalproperties of a novel, high affinity (4~2 nicotinicacetylcholine receptor ligand. Neuropharmacology1996;35:725-34.
7 Horti AG, Scheffel V, Koren AD, Ravert HT,Mathews WB, Musachio JL, et al. 2-C8F]FluoroA-85380, an in vivo tracer for the nicotinicacetylcholine receptors. Nucl Med Biol 1998;25:599-603.
8 Scheffel V, Horti AG, Koren AD, Ravert HT,Banta JP, Finliy PA. 6-C8F]Fluoro- A-85380: Anin vivo tracer for the nicotinic acetylcholinereceptor. Nucl Med Biol 2000; 27:51-6.
9 Abreo MA, Lin NH, Garvey DS, Gunn DE,Hettinger AM, Wasicak IT, et al. Novel3-pyridyl ethers with subnanomolar affinity forcentral nuronal nicotinic acetylcholine receptors.J Med Chem 1996;39:817-25.14.
10 Holladay MW, Dart MJ, Lynch JK. Neuronalnicotinic acetylcholine receptors as targets fordrug discovery. J Med Chem 1997;40:4169-94.
11 Musachio JL, Horti AG, London ED, DannalsRF. Synthesis of a radioiodinated analog ofepibatidine: (±)-Exo-2-(2-iodo-5-pyridy1)-7-azabicyclo[2.2.1]heptane for in vitro and in vivo studies ofnicotinic acetylcholine receptors. J Labelled CpdRadiopharm 1997;39:39-48.10.
12 Horti AG, Koren AD, Lee KS, Mukhin AG,Vaupel DB, Kimes AS, et al. Radiosynthesis andpreliminary evaluation of 5-[123/25I]iodo_ 3-(2(S)azetidinylmethoxy)pyridine: A radioligand fornicotinic acetylcholine receptors. Nucl Med Biol1999;26:175-82.
13 London ED, Waller SB, Wamsley JK. Autoradiographiclocalization of CH]nicotine bindingsites in the rat brain. Neurosci Lett 1985;53:179-84.
14 Molina P, Ding YS, Carrol FI, Liang F, VolkowN, Kuhar M, et aL CSF]Norchlorofluoroepibatidine(NEEP): Preclinical toxicologicalstudies. J Nucl Med 1997;38:287P (Abstract).
15 Henningfield JE, Woodson PP. Dose-relatedactions of nicotine on behavior and physiology:Review and implications for replacement therapyfor nicotine dependence. J Subst Abuse 1989;1:301-17.
16 Kimes AS, Horti AG, Contoreggi C, Chefer SI,Kurian V, Friello P, et al. Imaging human (4~2nicotinic receptors with PET. J Nucl Med2002;43S:356.
17 Spande TF, Garraffo HM, Edwards MW, YehHJC, Panell L, Daly JW. Epibatidine: A novel(chloropyridyl)azabicycloheptane with potentanalgesic activity from an Ecuadorian poison frog.J Am Chem Soc 1992;114: 3475-8.
18 Ding Y-S, Liu N, Wang T, Marecek J, Garza V,Ojima I, Fowler JS. Synthesis and evaluation of6-C8pjfluoro-3-(2(S)-azetidinylmethoxy) pyridineas a PET tracer for nicotinic acetylcholinereceptors. Nucl Med Biol 2000;27:381-9.
19 Horti AG, Scheffel D, Stathis M, Finley P,Ravert HT, London ED et aL eSF]FPH for PETimaging of nicotinic acetylcholine receptors. JNucl Med 1997;38:1260-5.
20 Decker MW, Brioni JD, Bannon AW, ArnericSP. Diversity of neuronal nicotinic actylcholinereceptor: Lessons from behavior and implicationsfor CNS therapeutics. Life Sci 1995;56:545-70.
21 Musachio, JL, Villemagne VL, Scheffel VA, Dannals RF, Dogan AS, Yokoi F, et al. Synthesis of an 1-123 analog of A-85380 and preliminary SPECT imaging of nicotinic receptors in baboon. Nucl Med Biol 1999;26:201-7.
22 Dolle F, Valette H, Bottlaender M, Hinnen F,Vaufrey F, Guenther I, et al. Synthesis of2-[18F]fluoro-3-[2(S)-azetidinylmethoxy]pyridine,a highly potent radioligand for in vivo imagingcentral nicotinic acetylcholine receptors. JLabelled Cpd Radiopharm 1998;41:451-63.
23 Horti AG, Ravert HT, London ED, Dannals RF.Synthesis of a radiotracer for studying nicotinicacetylcholine receptors: (±)-Exo-2-(2-[ISF]fluoro5-pyridyl)-7-azabicyclo[2.2.1]heptane. J LabelledCpd Radiopharm 1996;38:355-66.
24 Flicker KRL, Watkins KL, Fisher SK, BartusRT. Behavioral and neurochemical effectsfollowing neurotoxic lesions of a major cholinergicinput to cerebral cortex in rat. PharmacalBiochem Behav 1983;18:973- 81.
25 Pert A. Cholinergic and catecholaminergic modulationof nociceptive reactions: Interactionswith opiates. In: Akil A, Lewis JW, editors.Pain and Headache, Neurotransmitters and PainControl. Basel: Karger; 1987. p. 1-63.
26 Horti AG, Koren AD, Ravert HT, Musachio, JL,Mathews WB, London ED, et al. Synthesis of aradiotracer for studying nicotinic acetylcholinereceptors: 2-C8pjfluoro- 3-(2(S)-azetidinylmethoxy)pyridine(2-C8F] A-85380). J Labelled CpdRadiopharm 1998;41:309-18.