Background

[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 transporter (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-life 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) and showed slow tracer uptake kinetics (7, 8). A 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 DAT with PET imaging (9-11). N-4-[¹⁸F]Fluorobut-2-yn-1-yl-2β-carbomethoxy-3β-phenyltropane ([¹⁸F]PR04.MZ) was developed through the use of a conformational restriction approach based on (-)-cocaine (12). PR04.MZ exhibited a 100-fold higher potency than (-)-cocaine in inhibition of human DAT and better selectivity over the human noradrenalin transporter (hNET) and human serotonin transporter (hSERT). [¹⁸F]PR04.MZ has been evaluated as a radioligand for studies of DAT with PET imaging.

Synthesis

[PubMed]

[¹⁸F]PR04.MZ was readily synthesized by standard ¹⁸F-fluorination of the mesylate precursor with [¹⁸F]KF/Kryptofix 2.2.2 in acetonitrile for a few min at 120°C (12). [¹⁸F]PR04.MZ was purified with high-performance liquid chromatography. Overall radiochemical yield (non-decay corrected) was 13 ± 3%, with a specific activity of 18–95 GBq/µmol (0.5–2.6 Ci/µmol) at the end of synthesis and a radiochemical purity of >98%. Total synthesis time was 50 min.

In Vitro studies: Testing in Cells and Tissues

[PubMed]

PR04.MZ binding affinity for hDAT, hSERT, and hNET was determined using stably transfected HEK293 cells (12). [³H]β-CFT, [³H]citalopram, and [³H]nisoxetine were used as radioligands, respectively. The 50% inhibition concentration values for hDAT, hSERT, and hNET were 1.9 ± 0.2 nM, 108.4 ± 1.3 nM, and 22.5 ± 0.8 nM, respectively. In vitro autoradiography studies with [¹⁸F]PR04.MZ in rat brain sections showed a high radioactivity level in the striatum, with low binding in the cortical regions and cerebellum. Binding in the brain was totally blocked in the presence of 1 µM β-CFT.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

References

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Laruelle M., Wallace E., Seibyl J.P., Baldwin R.M., Zea-Ponce Y., Zoghbi S.S., Neumeyer J.L., Charney D.S., Hoffer P.B., Innis R.B. Graphical, kinetic, and equilibrium analyses of in vivo [123I] beta-CIT binding to dopamine transporters in healthy human subjects. J Cereb Blood Flow Metab. 1994;14(6):982–94. [PubMed: 7929662]

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Chalon S., Hall H., Saba W., Garreau L., Dolle F., Halldin C., Emond P., Bottlaender M., Deloye J.B., Helfenbein J., Madelmont J.C., Bodard S., Mincheva Z., Besnard J.C., Guilloteau D. Pharmacological characterization of (E)-N-(4-fluorobut-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (LBT-999) as a highly promising fluorinated ligand for the dopamine transporter. J Pharmacol Exp Ther. 2006;317(1):147–52. [PubMed: 16339913]

10.

Dolle F., Emond P., Mavel S., Demphel S., Hinnen F., Mincheva Z., Saba W., Valette H., Chalon S., Halldin C., Helfenbein J., Legaillard J., Madelmont J.C., Deloye J.B., Bottlaender M., Guilloteau D. Synthesis, radiosynthesis and in vivo preliminary evaluation of [11C]LBT-999, a selective radioligand for the visualisation of the dopamine transporter with PET. Bioorg Med Chem. 2006;14(4):1115–25. [PubMed: 16219467]

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Saba W., Valette H., Schollhorn-Peyronneau M.A., Coulon C., Ottaviani M., Chalon S., Dolle F., Emond P., Halldin C., Helfenbein J., Madelmont J.C., Deloye J.B., Guilloteau D., Bottlaender M. [11C]LBT-999: a suitable radioligand for investigation of extra-striatal dopamine transporter with PET. Synapse. 2007;61(1):17–23. [PubMed: 17068778]

12.

Riss P.J., Debus F., Hummerich R., Schmidt U., Schloss P., Lueddens H., Roesch F. Ex vivo and in vivo evaluation of [18F]PR04.MZ in rodents: a selective dopamine transporter imaging agent. ChemMedChem. 2009;4(9):1480–7. [PubMed: 19588472]