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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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, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim

Created: ; Last Update: July 24, 2006.

Chemical name:5-[123I]Iodo-3-[2(S)-2-azetidinylmethoxy]pyridineimage 12011213 in the ncbi pubchem database
Abbreviated name:5-[123I]IA
Agent Category:Compound
Target:Neuronal α4β2 nicotinic acetylcholine receptor (nAChR)
Target Category:Receptor binding
Method of detection:SPECT, planar
Source of signal:123I
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-human primates
  • Checkbox Humans
Click on the above structure for additional information in PubChem.



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) receptors. nAChRs have been to be involved in cognitive processes such as learning 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 other 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, 5). 6-[18F]Fluoro-A-85380 and 2-[18F]fluoro-A-85380 have been studied in humans as PET agents for α4β2 nAChR imaging in the brain. A-85380 has also been labeled as 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-[123I]iodo-A-85380). 5-[123I]iodo-A-85380 (5-[123I]IA) is being developed as a single photon emission computed tomography (SPECT) agent for the non-invasive study of nAChR in the brain.



Horti et al. (6) reported synthesis of 5-[123I]IA by a two-step procedure, which consisted of standard chloramine-T oxidative radioiodination of 5-trimethylstannyl-3-[1-tert-butoxycarbonyl-2(S)-azetidinyl)methoxy]pyridine and acidic deprotection of the product. Average radiochemical yields were 40-55% (end of synthesis). The average specific activity was 259 GBq/μmol (7 Ci/μmol at end of synthesis) with a radiochemical purity of >95%. Musachio et al. (7) reported a similar synthesis of 5-[123I]IA with a radiochemical yield of up to 52% and specific activities of >320 GBq/μmol (>8.5 Ci/μmol).

In Vitro Studies: Testing in Cells and Tissues


Sullivan et al. (5) reported that A-85380 had inhibition constant (Ki) values of 0.05 ± 0.01, 148 ± 13, and 314 ± 12 nM in human α4β2, α7, and muscle α1β1δγ receptors, respectively. A-85380 (up to 10,000 nM) has no effect in other neurotransmitter binding assays. Horti et al. (6) determined that 5-[123I]IA had a Kd (affinity constant) of 11.2 ± 0.3 pM and a Bmax (receptor density) of 134 ± 2 fmol/mg protein in rat forebrain homogenates. Saji et al. (8) reported that 5-IA, cytisine and nictotine had Ki values (obtained by use of 5-[125I]IA) of 0.40, 1.40 and 1.32 pM for α4β2 in rat brain membranes, respectively.

Animal Studies



Saji et al. (8) reported biodistribution studies of 5-[125I]IA in the rats, showing peak accumulation in the brain (1.05% injected dose/g(ID/g)) at 60 min. The kidney had the highest accumulation (5.09% ID/g), followed by the liver (1.55% ID/g), thyroid (0.44% ID/g), and heart (0.19% ID/g). All organs showed washout with time except the thyroid, which had a gradual increase to 2.35% ID/g at 180 min. The highest accumulation of radioactivity was observed in the thalamus (1.5% ID/g), followed by the cortex (1.2% ID/g), striatum (1.0% ID/g), and cerebellum (0.7% ID/g) at 60 min after injection of 5-[125I]IA. Nicotine and cytisine pretreatments significantly inhibited 5-[125I]IA binding in all regions of the brain, including the cerebellum. Scopolamine (a muscarinic AChR antagonist) did not exhibit any inhibition. Pretreatment with 5-IA (300 nmol/kg) blocked accumulation in the thalamus and cortex by 90% at 60 min and to a lesser extent in the cerebellum. The fraction of unchanged 5-[125I]IA in plasma was 60, 18, 13 and 3% at 5, 15, 30 and 60 min, respectively. Two hydrophilic metabolites were detected. The fraction of unchanged 5-[125I]IA in the brain was 90% at 60 min.

Vaupel et al. (9) performed biodistribution studies in mice after injection of 0.11 MBq (3 μCi) 5-[125I]IA (0.05 nmol/kg). 5-[125I]IA accumulation was higher in the thalamus (10% ID/g) and superior colliculus (10% ID/g) and lower in the cerebellum (2% ID/g) at 60 min after injection. The cortex, hippocampus and striatum had an intermediate level of uptake of 4-5% ID/g. A peak uptake was reached in the cerebellum at <5 min (earlier than most other brain regions), followed by a rapid washout. The thalamus/cerebellum ratio increased from 5 at 60 min to 37 at 240 min. Nicotine and cytisine pretreatments significantly inhibited 5-[125I]IA binding in all regions of the brain, with little inhibition in the cerebellum. Scopolamine did not exhibit any inhibition. Pretreatment with 5-IA (300 nmol/kg) blocked accumulation in the thalamus and cortex by >85%. Only marginal inhibition was observed in the cerebellum.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


5-[123I]IA SPECT studies with non-human primates showed substantial brain accumulation with selective maximal uptake in the regions of the thalamus and intermediate uptake in the striatum and cortex (7, 10, 11). The cerebellum showed lower binding than the other brain regions. 5-[123I]IA radioactivity was blocked (pretreatment) and displaced (injected after tracer) by A-85380, nicotine and cytisine. Using the one-tissue compartment model, Fujita et al. (11) estimated total distribution volume (VT’)values of 24.5–35.1 and 7.6-16.7 in the thalamus and cerebellum, respectively, of three baboons. Cytisine (0.8 and 1.0 mg/kg) showed displacement of 5-[123I]IA in the thalamus (70-72%) and cerebellum (36-55%) when administered less than 2 h after 5-[123I]IA injection. Therefore, the cerebellum is not suitable to be used as a receptor-poor region. The fraction of unchanged 5-[123I]IA in the plasma as determined by high-performance liquid chromatography (HPLC was 20-26% at 30 min after injection.

Human Studies


Fujita et al. (12) performed SPECT studies in six healthy nonsmoking subjects (age 33 ±15 years) with injection of 317 ± 42 MBq (8.6 ± 1.1 mCi) 5-[123I]IA. The study duration was 5-8 h. Nonlinear least-squares compartmental analysis was applied to calculate total (VT') and specific (VS') distribution volumes. VT' was well identified by both one- and two-tissue compartment models, with a coefficient of variation of <5% in most regions. The two-compartment model estimated VT' values of 51, 32, 27, 22, 20, 20, 19, and 17 ml/cm3 in the thalamus, pons, putamen, cerebellum, frontal cortex, temporal cortex, parietal cortex, and occipital cortex, respectively. SPECT studies were also performed on the same six subjects with a bolus plus constant infusion (B/I) (total dose: 331 ± 55 MBq, 8.9 ± 1.5 mCi). B/I studies did not provide accurate assessment of VT' values because of deviations from equilibrium conditions as a result of variable B/I ratio. Later, Staley et al. (13) and Mamede et al. (14) reported reproducible and reliable results were obtained using B/I equilibrium imaging by using constant B/I ratio and 2-compartment model with graphical analyses in healthy nonsmoking subjects.

Human dosimetry of 5-[123I]IA was estimated in ten normal volunteers (five males and five females) by Fujita et al. (15). Dynamic whole-body PET scans were acquired after the injection of 98 ± 6 MBq (2.65 ± 0.16 mCi, 0.53 ± 0.03 nmol) of 5-[123I]IA. There were no reported pharmacological effects associated with the 5-[123I]IA dosages. Uptake of 5-[123I]IA in the brain reached a peak of 5.0%ID within 14 min after injection. The greatest accumulation of 5-[123I]IA was in the thalamus, followed by the midbrain and pons. About 50% ID was excreted in urine in 8 h. The organ with the highest absorbed dose was found to be the urinary bladder (140 µGy/MBq (518 mrad/mCi)), followed by the lower large intestine wall (72 µGy/MBq (266 mrad/mCi)), upper large intestine wall (64 µGy/MBq (237 mrad/mCi)), kidney (54 µGy/MBq (199 mrad/mCi)), and liver (45 µGy/MBq (167 mrad/mCi)). The effective dose equivalent was calculated to be 32 µSv/MBq (0.12 rem/mCi). Ueda et al. (16) estimated the effective dose equivalent to be 30 µSv/MBq (0.11 rem/mCi) in another study of healthy volunteers.


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