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| Chemical name: | 8-((E)-4-Fluoro-but-2-enyl)-3β-p-tolyl-8-aza-bicyclo[3.2.1]octane-2β-carboxylic acid [11C]methyl ester |  |
| Abbreviated name: | [11C]LBT-999 | |
| Synonym: | [11C]-(E)-N-(4-Fluorobut-2-enyl)-2β-carbomethoxy-3β-(4'-tolyl)nortropane | |
| Agent category: | Compound | |
| Target: | Dopamine transporter (DAT) | |
| Target category: | Binding to dopamine transporter | |
| Method of detection: | PET | |
| Source of signal: | 11C | |
| Activation: | No | |
| Studies: |
| Click on the above structure for additional information in PubChem. |
[PubMed]
Dopamine, a neurotransmitter, plays an important role in the mediation of movement, cognition, and emotion. Parkinson’s disease (PD) is associated with a loss of dopamine-containing neurons in the striatum, resulting in a loss of dopamine transporters (DAT) in the presynaptic nerve terminals (1, 2). Reduction of DAT density is inversely correlated with the severity of motor dysfunction in PD patients. Several cocaine analogs were developed for the evaluation of DAT density in neurons of PD patients. Radiolabeled 2β-carboxymethoxy-3β-(4-iodophenyl)tropane (β-CIT) and N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT) have been used for brain imaging (3-6). Because of the short physical half-live of 11C- of 11C-labeled analogs, equilibrium conditions are difficult to achieve in positron emission tomography (PET) measurements. [123I]β-CIT was studied in single photon emission computed tomography (SPECT), which showed slow tracer uptake kinetics (7, 8). A new tropane derivative, [11C]-(E)-N-(4-fluorobut-2-enyl)-2β-carbomethoxy-3β-(4'-tolyl)nortropane ([11C]LBT-999), was evaluated as a radioligand for studies of the dopamine transporter (DAT) with PET imaging (9-11).
[PubMed]
[11C]LBT-999 was synthesized by a standard methylation reaction of its corresponding carboxylic acid precursor with [11C]methyl triflate (10). The radiochemical yield was 19-45% (n = 10) based on [11C]CO2. The radiochemical purity was >99% with specific activities of 30-45 GBq/µmol (0.81-1.22 Ci/µmol) at the end of synthesis. The total synthesis time was 25-30 min.
[PubMed]
Using in vitro binding experiments on rat striatal membranes, Dolle et al. (10) showed that [3H]LBT-999 bound to a single site with a Kd value of 9 nM and a Bmax value of 17 pmol/mg protein and displayed a very high selectivity for the DAT. The IC50 values were 2.4 and 18 nM for GBR 12909 and PE2I (DAT-selective inhibitors), respectively. The IC50 values for paroxetine, citalopram, nisoxetine and desipramine were >1 μM. Autoradiographic studies with [3H]LBT-999 in human post-mortem brain sections showed high radioactivity level in the putamen and caudate with weak binding in the thalamus and little binding in the cortical regions (9). The bindings in the brain were totally blocked in the presence of 10 µM PE2I.
Chalon et al. (9) performed biodistribution studies in rats (n = 4/group) at 10, 30, and 60 min after injection of 2.22 MBq (0.06 mCi) with the radioactivity level in the striatum was 4.90, 4.95 and 3.37% injected dose/g (ID/g), respectively. The striatum/cerebellum radioactivity ratio was 7, 18 and 25 at 10, 30 and 60 min after injection, respectively. Weak radioactivity was observed in the cerebellum (<0.3% ID/g) and cortex (~0.6% ID/g) at 30 min after injection. Pre-administration of the DAT inhibitor GBR 12909 (5 mg/kg) inhibited the binding in the striatum by ~70%, whereas paroxetine (serotonin transporter inhibitor) and nisoxetine (norepinephrine transporter inhibitor) exhibited little inhibition.
[PubMed]
Chalon et al. (9) performed PET studies in a baboon after injection of 419 MBq (11.3 mCi) [11C]LBT-999. The highest accumulation was observed in the putamen and caudate with a peak uptake at 40 min (16.3 and 13.3% ID/100 ml, respectively). The washout was slow from 30-80 min. Radioactivity accumulation in the midbrain peaked at 12 min (6.9% ID/100 ml) and decreased with time. The lowest accumulation was observed in the cortex and cerebellum (1.37 and 1.09% ID/100 ml, respectively). The putamen/cerebellum, caudate/cerebellum, midbrain/cerebellum, thalamus/cerebellum and cortex/cerebellum ratio was 30, 25, 6, 2 and 1, respectively. Dolle et al. (10) showed injection of PE2I (1 mg/kg) at 80 min after injection of [11C]LBT-999 in a baboon decreased the radioactivity level in the caudate, putamen and thalamus by 74-81% compared to the control at 2 hours. Saba et al. (11) extended the PET studies in five baboons using Logan (distribution volume), one tissue compartment model (distribution volume) and simplified tissue model (binding potential). The distribution volume of the various brain regions determined by one tissue kinetic model was similar to those obtained using the Logan graphical analysis. The simplified tissue model using the cerebellum as a reference tissue estimated the binding potential of the putamen, caudate, midbrain, thalamus and cortex to be 24.7, 22.4, 2.4, 0.7 and 0.1, respectively. The serotonin transporter antagonist citalopram (5 mg/kg) or the norepinephrine transporter antagonist maprotiline (5 mg/kg) had little effect on the binding potential in these brain regions. On the other hand, PE2I (1 mg/kg, pretreatment) induced an almost complete inhibition of the binding potential in the putamen (96%), caudate (96%), midbrain (92%), and thalamus (71%). The fraction of unchanged [11C]LBT-999 in plasma samples was 25% at 30 min after injection with two polar metabolites.
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