Characterization of the nicotinic ligand 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine in vivo

doi:10.1016/S0024-3205(98)00573-6

Life Sciences

Volume 64, Issue 5, 24 December 1998, Pages PL93-PL97

https://doi.org/10.1016/S0024-3205(98)00573-6 Get rights and content

Abstract

The biodistribution of the nicotinic acetylcholine receptor (nAChR) radioligand 2-[¹⁸F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine ([¹⁸F]fluoro-A-85380, half-life of fluorine-18 = 110 min) in selected rat brain areas was assessed in vivo. The radiotracer showed a good penetration in the brain. The regional distribution of the radioligand was consistent with the density of nAChRs determined from previous studies in vitro. Sixty minutes post-injection, the highest uptake was observed in the thalamus, (1% I.D. /g tissue), an intermediate one in the frontal cortex (0.78% I.D. /g tissue), and the lowest in the cerebellum (0.5% I.D. /g tissue). Pretreatment with several nAChR ligands (nicotine, cytisine, epibatidine, unlabeled fluoro-A-85380) substantially reduced uptake of the radioligand in the three cerebral areas. Pretreatment with the nAChR channel blocker mecamylamine or with the muscarinic receptor antagonist dexetimide had no appreciable effect on the uptake of fluoro-A-85380. These results support the high in vivo selectivity and specificity of fluoro-A-85380. Therefore, [¹⁸F]fluoro-A-85380 may be useful for positron emission tomography study of nAChRs in humans.

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Cited by (27)

Dual role of nicotine in addiction and cognition: A review of neuroimaging studies in humans
2014, Neuropharmacology
Citation Excerpt :
For examining the acute and chronic effects of cigarette smoking, PET and SPECT scanning have been performed in human smokers, with the most commonly used radiotracers being 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (abbreviated as 2-FA) for PET scanning (Koren et al., 1998) and 123-labeled 5-iodo-A-85380 (abbreviated as 5-IA) for SPECT scanning (Horti et al., 1999). These radiotracers bind with high affinity and relative specificity to α4β2∗ nAChRs (Koren et al., 1998), and the safety and reliability of these radiotracers have been verified (Bottlaender et al., 2003; Chefer et al., 2003; Fujita et al., 2002; Kimes et al., 2008; Valette et al., 1999). In examining the acute effects of smoking/nicotine administration, 2-FA PET and 5-IA SPECT studies have demonstrated the effect of cigarette smoking on α4β2∗ nAChR occupancy.
Substantial evidence demonstrates both nicotine's addiction liability and its cognition-enhancing effects. However, the neurobiological mechanisms underlying nicotine's impact on brain function and behavior remain incompletely understood. Elucidation of these mechanisms is of high clinical importance and may lead to improved therapeutics for smoking cessation as well as for a number of cognitive disorders such as schizophrenia. Neuroimaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI), which make it possible to study the actions of nicotine in the human brain in vivo, play an increasingly important role in identifying these dual mechanisms of action. In this review, we summarize the current state of knowledge and discuss outstanding questions and future directions in human neuroimaging research on nicotine and tobacco. This research spans from receptor-level PET and SPECT studies demonstrating nicotine occupancy at nicotinic acetylcholine receptors (nAChRs) and upregulation of nAChRs induced by chronic smoking; through nicotine's interactions with the mesocorticolimbic dopamine system believed to mediate nicotine's reinforcing effects leading to dependence; to functional activity and connectivity fMRI studies documenting nicotine's complex behavioral and cognitive effects manifest by its actions on large-scale brain networks engaged both during task performance and at rest.
This article is part of the Special Issue Section entitled ‘Neuroimaging in Neuropharmacology’.
Functional brain imaging of tobacco use and dependence
2006, Journal of Psychiatric Research
While most cigarette smokers endorse a desire to quit smoking, only about 14% to 49% will achieve abstinence after 6 months or more of treatment. A greater understanding of the effects of smoking on brain function may (in conjunction with other lines of research) result in improved pharmacological (and behavioral) interventions. Many research groups have examined the effects of acute and chronic nicotine/cigarette exposure on brain activity using functional imaging; the purpose of this paper is to synthesize findings from such studies and present a coherent model of brain function in smokers. Responses to acute administration of nicotine/smoking include: a reduction in global brain activity; activation of the prefrontal cortex, thalamus, and visual system; activation of the thalamus and visual cortex during visual cognitive tasks; and increased dopamine (DA) concentration in the ventral striatum/nucleus accumbens. Responses to chronic nicotine/cigarette exposure include decreased monoamine oxidase (MAO) A and B activity in the basal ganglia and a reduction in α₄β₂ nicotinic acetylcholine receptor (nAChR) availability in the thalamus and putamen. Taken together, these findings indicate that smoking enhances neurotransmission through cortico-basal ganglia-thalamic circuits either by direct stimulation of nAChRs, indirect stimulation via DA release or MAO inhibition, or a combination of these factors. Activation of this circuitry may be responsible for the effects of smoking seen in tobacco dependent subjects, such as improvements in attentional performance, mood, anxiety, and irritability.
Synthesis and radiosynthesis of [18F]FPhEP, a novel α<inf>4</inf>β<inf>2</inf>-selective, epibatidine-based antagonist for PET imaging of nicotinic acetylcholine receptors
2006, Bioorganic and Medicinal Chemistry
FPhEP (1, (+/−)-2-exo-(2′-fluoro-3′-phenyl-pyridin-5′-yl)-7-azabicyclo[2.2.1]heptane) belongs to a recently described novel series of 3′-phenyl analogues of epibatidine, which not only possess subnanomolar affinity and high selectivity for brain α4β2 neuronal nicotinic acetylcholine receptors (nAChRs), but also were reported as functional antagonists of low toxicity (up to 15 mg/kg in mice). FPhEP (1, K_i of 0.24 nM against [³H]epibatidine) as reference as well as the corresponding N-Boc-protected chloro- and bromo derivatives (3a,b) as precursors for labelling with fluorine-18 were synthesized in eight and nine steps, respectively, from commercially available N-Boc-pyrrole (overall yields = 17% for 1, 9% for 3a and 8% for 3b). FPhEP (1) was labelled with fluorine-18 using the following two-step radiochemical process: (1) no-carrier-added nucleophilic heteroaromatic ortho-radiofluorination from the corresponding N-Boc-protected chloro- or bromo derivatives (3a,b—1 mg) and the activated K[¹⁸F]F–Kryptofix^®₂₂₂ complex in DMSO using microwave activation at 250 W for 1.5 min, followed by (2) quantitative TFA-induced removal of the N-Boc-protective group. Radiochemically pure (>99%) [¹⁸F]FPhEP ([¹⁸F]-1, 2.22–3.33 GBq, 66–137 GBq/μmol) was obtained after semi-preparative HPLC (Symmetry^® C18, eluent aq 0.05 M NaH₂PO₄/CH₃CN, 80:20 (v:v)) in 75–80 min starting from a 18.5 GBq aliquot of a cyclotron-produced [¹⁸F]fluoride production batch (10–20% nondecay-corrected overall yield). In vitro binding studies on rat whole-brain membranes demonstrated a subnanomolar affinity (K_D 660 pM) of [¹⁸F]FPhEP ([¹⁸F]-1) for nAChRs. In vitro autoradiographic studies also showed a good contrast between nAChR-rich and -poor regions with a low non-specific binding. Comparison of in vivo Positron Emission Tomography (PET) kinetics of [¹⁸F]FPhEP ([¹⁸F]-1) and [¹⁸F]F-A-85380 in baboons demonstrated faster brain kinetics of the former compound (with a peak uptake at 20 min post injection only). Taken together, the preliminary data obtained confirm that [¹⁸F]FPhEP ([¹⁸F]-1) has potential for in vivo imaging nAChRs in the brain with PET.
Simplified quantification of nicotinic receptors with 2[ 18F]F-A-85380 PET
2005, Nuclear Medicine and Biology
Neuronal nicotinic acetylcholine receptors (nAChRs), widely distributed in the human brain, are implicated in various neurophysiological processes as well as being particularly affected in neurodegenerative conditions such as Alzheimer's disease. We sought to evaluate a minimally invasive method for quantification of nAChR distribution in the normal human brain, suitable for routine clinical application, using 2[¹⁸F]F-A-85380 and positron emission tomography (PET).
Ten normal volunteers (four females and six males, aged 63.40±9.22 years) underwent a dynamic 120-min PET scan after injection of 226 MBq 2[¹⁸F]F-A-85380 along with arterial blood sampling. Regional binding was assessed through standardized uptake value (SUV) and distribution volumes (DV) obtained using both compartmental (DV_2CM) and graphical analysis (DV_Logan). A simplified approach to the estimation of DV (DV_simplified), defined as the region-to-plasma ratio at apparent steady state (90–120 min post injection), was compared with the other quantification approaches.
DV_Logan values were higher than DV_2CM. A strong correlation was observed between DV_simplified, DV_Logan (r=.94) and DV_2CM (r=.90) in cortical regions, with lower correlations in thalamus (r=.71 and .82, respectively). Standardized uptake value showed low correlation against DV_Logan and DV_2CM.
DV_simplified determined by the ratio of tissue to metabolite-corrected plasma using a single 90- to 120-min PET acquisition appears acceptable for quantification of cortical nAChR binding with 2[¹⁸F]F-A-85380 and suitable for clinical application.
Synthesis of a [2-Pyridinyl-18F]-labelled fluoro derivative of (-)-cytisine as a candidate radioligand for brain nicotinic α4β2 receptor imaging with PET
2003, Bioorganic and Medicinal Chemistry
In recent years, there has been considerable effort to design and synthesize radiotracers suitable for use in Positron Emission Tomography (PET) imaging of the α4β2 neuronal nicotinic acetylcholine receptor (nAChR) subtype. A new fluoropyridinyl derivative of (−)-cytisine (1), namely (−)-9-(2-fluoropyridinyl)cytisine (3, K_i values of 24 and 3462 nM for the α4β2 and α7 nAChRs subtypes, respectively) has been synthesized in four chemical steps from (−)-cytisine and labelled with fluorine-18 (T_1/2: 119.8 min) using an efficient two-step radiochemical process [(a) nucleophilic heteroaromatic ortho-radiofluorination using the corresponding N-Boc-protected nitro-derivative, (b) TFA removal of the Boc protective group]. Typically, 20–45 mCi (0.74–1.67 GBq) of (−)-9-(2-[¹⁸F]fluoropyridinyl)cytisine ([¹⁸F]-3, 2–3 Ci/μmol or 74–111 GBq/μmol) were easily obtained in 70–75 min starting from a 100 mCi (3.7 GBq) aliquot of a cyclotron-produced [¹⁸F]fluoride production batch (20–45% non decay-corrected yield based on the starting [¹⁸F]fluoride). The in vivo pharmacological profile of (−)-9-(2-[¹⁸F]fluoropyridinyl)cytisine ([¹⁸F]-3) was evaluated in rats with biodistribution studies and brain radioactivity monitoring using intracerebral radiosensitive β-microprobes. The observed in vivo distribution of the radiotracer in brain was rather uniform, and did not match with the known regional densities of nAChRs. It was also significantly different from that of the parent compound (−)-[³H]cytisine. Moreover, competition studies with (−)-nicotine (5 mg/kg, 5 min before the radiotracer injection) did not reduce brain uptake of the radiotracer. These experiments clearly indicate that (−)-9-(2-[¹⁸F]fluoropyridinyl)cytisine ([¹⁸F]-3) does not have the required properties for imaging nAChRs using PET.
Fluoro-A-85380 demonstrated no mutagenic properties in in vivo rat micronucleus and Ames tests
2002, Nuclear Medicine and Biology
The potential mutagenic properties (micronucleus and the Ames tests) of fluoro-A-85380 (2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine) were evaluated as a mandatory pre-clinical step. No statistically significant increase in the frequency of micronucleated polychromatic erythrocytes was found in animals treated at any dose tested. No biologically significant increase in the mean number of revertants was noted in all the Salmonella typhimurium strains tested with fluoro-A-85380. Therefore, fluoro-A-85380 demonstrated no mutagenic properties using these two tests.

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^∗: Héric Valette, Service Hospitalier Frédéric Joliot, DSV/DRM-CEA, 4 Place du Général Leclerc. 91406 Orsay, France. Phone: 33 (1) 69 86 77 02 Fax: 33 (1) 69 86 77 68).

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Abstract

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Cited by (27)

Dual role of nicotine in addiction and cognition: A review of neuroimaging studies in humans

Functional brain imaging of tobacco use and dependence

Synthesis and radiosynthesis of [<sup>18</sup>F]FPhEP, a novel α<inf>4</inf>β<inf>2</inf>-selective, epibatidine-based antagonist for PET imaging of nicotinic acetylcholine receptors

Simplified quantification of nicotinic receptors with 2[ <sup>18</sup>F]F-A-85380 PET

Synthesis of a [2-Pyridinyl-<sup>18</sup>F]-labelled fluoro derivative of (-)-cytisine as a candidate radioligand for brain nicotinic α4β2 receptor imaging with PET

Fluoro-A-85380 demonstrated no mutagenic properties in in vivo rat micronucleus and Ames tests

Pharmacology letter Accelerated communicationCharacterization of the nicotinic ligand 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine in vivo

Abstract

Nucl. Med. Biol.

Life Sci.

Nucl. Med. Biol.

Neuropharmacol.

Neurosci.

Brain. Res.

Prog. Neurobiol.

Eur. J. Nucl. Med.

Psychopharmacol.

Nucl. Med. Com.

Mol. Pharmacol.

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Pharmacology letter Accelerated communication
Characterization of the nicotinic ligand 2-[¹⁸F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine in vivo