PET imaging of dopamine transporters in the human brain using [ 11C]-β-CPPIT, a cocaine derivative lacking the 2β-ester function

The compound 3β-(4′-chlorophenyl)-2β-(3′-phenylisoxazol-5′-yl)tropane (CPPIT or RTI 177) is a 2β-heterocyclic substituted cocaine congener with high in vitro selectivity and affinity for the dopamine transporter relative to serotonin and norepinephrine transporters. The aim of the present study was to evaluate the in vivo selectivity of [ 11C]-β-CPPIT and to determine whether [ 11C]-β-CPPIT may be a suitable alternative to existing DAT PET radioligands. [ 11C]-β-CPPIT was prepared by N-alkylation of the free amine with [ 11C]methyl iodide. In mouse brain, the striatal binding of [ 11C]-β-CPPIT was reduced significantly by preinjecting the dopamine reuptake antagonist GBR 12909 (5 mg/kg). By contrast, radioactivity uptake in the brain was not affected significantly by the preinjection of citalopram (5 mg/kg) and desipramine (5 mg/kg), inhibitors for the serotonin and norepinephrine transporters, respectively. No effect was also observed by pretreatment with ketanserin (2.5 mg/kg) a compound with high affinity for the 5-HT 2A-receptor and the vesicular monoamine transporter. In a PET study with six healthy volunteers high striatal uptake was observed. The distribution pattern of [ 11C]-β-CPPIT was similar to the known distribution of the dopamine transporter in the human brain. Compared to 123I labeled β-CIT, the rate of metabolic degradation of [ 11C]-β-CPPIT was almost twofold slower suggesting that bioisosteric heterocyclic substitution of the ester group at the 2β-position of the tropane ring does have an influence on the rate of metabolism of [ 11C]-β-CPPIT. The rank order of the distribution volumes obtained via the one-tissue compartment model is also similar to the reported distribution of DAT. These preliminary results suggest that [ 11C]-β-CPPIT may be a useful PET radioligand for the visualization and quantification of dopamine transporters in man.