Dopamine transporter (DAT) occupancy by pyrovalerone analogs: A novel class of potentially abusable drugs

Objectives Compounds that affect DAT have therapeutic but also abuse potential. The stimulant pyrovalerone is a relatively high affinity DAT inhibitor with limited therapeutic uses because of abuse liability. We developed a series of pyrovalerone analogs with the view of reducing the abuse liability. As several compounds bound the dopamine, norepinephrine and serotonin transporters within the therapeutic range, we assessed their therapeutic potential further, by PET.

Methods To monitor DAT occupancy, PET was conducted with the high affinity DAT probe ¹¹C CFT. DAT density (binding potential, BP) was measured in rhesus monkeys to obtain baseline DAT levels. The test compound was then administered I.V and PET with a second injection of CFT was performed 1 hr later. Occupancy was calculated on the basis of reduced BP.

Results These compounds exhibited high to moderate DAT potency (3.1-216 nM) and moderate to high DAT:SERT selectivity. All compounds (1 mg/kg) occupied ≥59% of striatal DAT sites. Intriguingly, several compounds with high in vitro DAT affinity, predicted to occupy a significant proportion of DAT sites, showed lower DAT occupancy than lower affinity compounds, within the time frame of the study. Several compounds that displayed modest affinity for the DAT (O-2443, O-2439) occupied a high proportion of DAT sites, comparable to compounds with considerably higher DAT affinity. DAT occupancy was correlated with logP values (lipophilicity) and not with DAT affinity.

Conclusions For this series of compounds, in vitro affinity data did not accurately predict DAT occupancy, as measured by PET. Slow onset (DAT occupancy at later times) could converge in vitro/in vivo data. With the current data, PET identified compounds with rapid onset, relevant both for therapeutic efficacy and abuse liability. An unintended consequence was the clandestine manufacture and sale of one analog O-2482 (naphyrone) as a “street drug”