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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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2-[18F]Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine

2-[18F]FA
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim

Created: ; Last Update: April 8, 2008.

Chemical name:2-[18F]Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridineimage 11538006 in the ncbi pubchem database
Abbreviated name:2-[18F]FA
Synonym:2-[18F]Fluoro-A-85380
Agent Category:Compound
Target:α4β2 nicotinic acetylcholine receptor (nAChR)
Target Category:Receptor binding
Method of detection:PET
Source of signal:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-human primates
  • Checkbox Humans
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Neuronal nicotinic cholinergic receptors (nAChRs) are a heterogeneous family of ligand-gated ion channels expressed in the central nervous system, where their activation by acetylcholine and nicotine always causes a rapid increase in cellular permeability to ions, such as Na+ and Ca2+ (1-3). Nicotinic receptors exist as pentamers (homomeric or heteromeric) in various brain regions and ganglia. There are nine subtypes of ligand-binding α (α2-α10) and four subtypes of structural β (β2-β5). nAChRs have been demonstrated to be involved in cognitive processes such as learning and memory and control of movement in normal subjects. Dysfunction of nAChR has been implicated to a number of human diseases such as schizophrenia, Huntington's disease, Alzheimer's disease (AD) and Parkinson's disease. nAChRs also play a significant role in nicotine addiction and related health problems associated with tobacco smoking.

3-[2(S)-2-azetidinylmethoxy]pyridine (A-85380) is a highly potent and selective α4β2 nAChR agonist with subnanomolar affinity (4). A-85380 has been labeled as 2-[18F]Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-[18F]fluoro-A-85380) (5). 2-[18F]fluoro-A-85380 (2-[18F]FA) is being developed as a positron emission tomography (PET) agent for the non-invasive study of nAChR in the brain.

Synthesis

[PubMed]

Horti et al. (5) reported synthesis of 2-[18F]FA by a 2-step reaction, which consisted of standard ([18F]KF/Kryptofix 2.2.2) 18F-nucleophilic aromatic fluorination of 2-iodo-3-[2-((S)-N-tert-butoxycarbonyl-3-pyrroline)methoxy]pyridine and acidic deprotection of the product. An average radiochemical yield was 10% (end of synthesis, based on [18F]KF) with a total synthesis time of 120 min. The average specific activity was 39 GBq/μmol (1.05 Ci/μmol at end of synthesis) with a radiochemical purity of >99%.

Dolle et al. (6) improved the radiochemical yields of 2-[18F]FA by using 2-nitro-3-[2-((S)-N-tert-butoxycarbonyl-2-azetidinymethoxy]pyridine for 18F-nucleophilic aromatic fluorination with the total synthesis time of 50-53 min (end of bombardment). The average radiochemical yields were 49-52% with the specific activities of 111-185 GBq/μmol (3-5 Ci/μmol at end of synthesis) and radiochemical purity of >99%. Trimethylammonium trifluoromethanesulfonate could also be used as the leaving group for the 18F-nucleophilic aromatic substitution with similar results. Schmaljohann et al. (7) has automated the synthesis of 2-[18F]FA with 58% yield in 45 min using the trimethylammonium trifluoromethanesulfonate precursor with specific activity >55 GBq/μmol (>1.5 Ci/μmol) at end of bombardment.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Sullivan et al. (4) reported that A-85380 had Ki values of 0.05 ± 0.01, 148 ± 13, and 314 ± 12 nM for human α4β2, α7, and muscle α1β1δγ receptors, respectively. A-85380 (up to 10,000 nM) has no effect in various neurotransmitter binding assays. Chefer et al. (8) determined that 2-[18F]FA had a Kd of 0.05 ± 0.003 nM and a Bmax of 140 ± 5 fmol/mg protein in rat brain homogenates.

Schmaljohann et al. (7) performed in vitro autoradiography studies of rat brain slices indicated selective binding of 2-[18F]FA to thalamus >striatum>cortex >cerebellum, consistent with α4β2 receptor distribution. The ratios of specific binding to total binding in cerebellum were 3.58, 1.25, and 1.02 for the thalamus, striatum, and cortex, respectively. Nicotine (10 μM) blocked 2-[18F]FA specific binding across the brain regions. In postmortem human brain sections of AD (n = 2), there was a decrease in 2-[18F]FA binding in the thalamus (32-40%) and occipital cortex (15-57%) but not in the entorhinal cortex compared with the control brains (n = 2). In the control brain sections, the radioactivity in the thalamus was 1.5 times higher than the occipital cortex and entorhinal cortex.

Animal Studies

Rodents

[PubMed]

Horti et al. (5) performed biodistribution studies in mice after injection of 0.74-1.11 MBq (20-30 μCi) 2-[18F]FA (1 nmol/kg). A peak uptake of 1.86% injected dose (ID)/g was reached in the whole brain at 15 min, followed by a gradual washout to 0.19% ID/g at 180 min. 2-[18F]FA accumulation was higher in the thalamus (7.2% ID/g) and in superior colliculus (6.8% ID/g) and lower in the hippocampus (~1.8% ID/g) and cerebellum (~1.0% ID/g) at 30 min post injection. Nicotine or cytosine pretreatment significantly inhibited 2-[18F]FA binding in all regions of the brain, with marginal inhibition in the cerebellum. Scopolamine (a muscarinic AChR antagonist) did not exhibit any inhibition. Pretreatment with 2-fluoro-A-85380 (170 nmol/kg) blocked accumulation in the striatum, parietal cortex, thalamus and superior colliculus by 43, 75, 84, and 85%, respectively. Only marginal inhibition was observed in the cerebellum and hippocampus. Vaupel et al. (9) estimated binding potential (BP) values in the brain of rats with 2-[18F]FA PET imaging using free arterial plasma levels. The BP values for thalamus, forebrain, and cerebellum were 5.9 ± 0.7, 2.6 ± 0.4, and 1.0 ± 0.1, respectively.

Other Non-Primate Mammals

[PubMed

No publication is currently available.

Non-Human Primates

[PubMed]

2-[18F]FA PET studies with non-human primates showed substantial brain accumulation with selective maximal uptake in the regions of the thalamus, intermediate uptake in the striatum and cortex (6, 8, 10). The cerebellum showed lower binding than the other brain regions. 2-[18F]FA radioactivity was blocked (pretreatment) and displaced by A-85380, nicotine and cytisine. Using graphical methods with arterial input function, Chefer et al. (11) estimated binding potential (BP) values of 2.0, 0.4, 0.3, and 0.03 observed in the thalamus, cortex, striatum, and cerebellum, respectively. For accurate quantization of [18F]FA specific binding by graphical analysis, PET studies should last up to 7 hours because of the slow kinetics of 2-[18F]FA brain distribution. The fraction of unchanged 2-[18F]FA in the plasma determined by HPLC was 50% at 60 min after injection. Two major hydrophilic metabolites were found.

Valette et al. (12) reported that physostigmine, a potent AChE inhibitor, inhibited the distribution volumes in the striatum, temporal cortex and frontal cortex (regions of interests) by 40, 23, and 30% in 2-[18F]FA PET studies in monkeys, respectively. The authors suggested that the effects of physostigmine may be the results of increased concentrations of synaptic acetylcholine, which could desensitize the nAChR and compete with 2-[18F]FA.

Human Studies

[PubMed]

Human dosimetry of 2-[18F]FA was estimated in six normal volunteers ( three males and three females) by Kimes et al. (13). Dynamic whole-body PET scans were acquired after the injection of 1.6 ± 0.07 MBq/kg (0.043 ± 0.002 mCi/kg, 5 ± 2 pmol/kg) of 2-[18F]FA. There were no reported pharmacological effects associated with the 2-[18F]FA administrations. Uptake of 2-[18F]FA in the brain reached a peak of 2.5%ID within 50-80 min after injection. The greatest accumulation of 2-[18F]FA was in the thalamus, followed by the midbrain and pons. About 89-93% of ID was excreted in urine. The organ that received the highest absorbed dose equivalent was found to be the urinary bladder (180 µSv/MBq or 0.66 rem/mCi) and all other organs (<51 µSv/MBq or 0.19 rem/mCi). The effective dose equivalent was calculated as 45 µSv/MBq (0.17 rem/mCi). Bottlaender et al. (14) estimated effective dose equivalent to be 20 µSv/MBq (0.074 rem/mCi) in a study of three male healthy volunteers.

NIH Support

Intramural Research Program

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