(1,2,3,5)-Methyl-8-{[(1,2)-2-([F]fluoromethyl)cyclopropyl]methyl}-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate

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 -(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 C-labeled analogs, equilibrium conditions are difficult to achieve in positron emission tomography (PET) measurements. [I]β-CIT was studied in single-photon emission computed tomography (SPECT) and showed slow tracer uptake kinetics (7, 8). A tropane derivative, [C]-()--(4-fluorobut-2-enyl)-2β-carbomethoxy-3β-(4'-tolyl)nortropane ([C]LBT-999), was evaluated as a radioligand for studies of DAT with PET imaging (9-11). [1,2,3,5]-Methyl-8-{[(1S, 2S)-2-([F]fluoromethyl)cyclopropyl]methyl}-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate ([F]PR17.MZ) was developed through the use of a conformational restriction approach based on (-)-cocaine. PR17.MZ exhibited a 29-fold higher potency than (-)-cocaine in inhibition of human DAT and better selectivity over the human noradrenalin transporter (hNET) and human serotonin transporter (hSERT) (12). [F]PR17.MZ has been evaluated as a radioligand for studies of DAT with PET imaging.