RTI-112

RTI-112 is a synthetic stimulant drug from the phenyltropane family. It is primarily used in scientific research to study the brain's reward system. In contrast to more well-known stimulants that primarily affect one type of brain cell communication, RTI-112 is a nonselective triple reuptake inhibitor. This means it simultaneously affects three important brain chemicals: serotonin, dopamine, and norepinephrine.
In vitro tests show a very similar serotonin transporter /dopamine transporter /norepinephrine transporter selectivity to cocaine, although in vivo behaviour is different:

"The nonselective monoamine transporter inhibitor RTI-126 and the DAT-selective inhibitors RTI-150 and RTI-336 both had a faster rate of onset and a short duration of action. In contrast, the nonselective monoamine transporter inhibitor RTI-112 had a slower rate of onset and a longer duration of action. The DAT-selective inhibitors RTI-171 and RTI-177 also had slower rates of onset, but RTI-171 had a short duration of action while RTI-177 had a very long duration of action."

The efficacy of cocaine analogs to elicit self-administration is related to the rate at which they are administered. Slower onset analogs are less likely to function as behavioral stimulants than analogs eliciting a faster rate of onset. Nonselective analogs are less likely to function as "reinforcers" than reuptake inhibitors that have DAT specificity.
In order for a dopamine reuptake inhibitor such as cocaine to induce euphoria, PET scans on primates reveal that the DAT occupancy needs to be >60%.
RTI-112 has equipotent in vitro affinity at the SERT, NET and DAT, respectively. RTI-112 was not reliably self-administered, in contrast to the DAT selective reuptake inhibitors that were used in this study.
In vivo at the ED50, RTI-112 had no DAT occupancy at all. At the ED50, almost all of the RTI-112 occupied the SERT at this dose. A significantly higher dose was required to get >70% DAT occupancy in the case of RTI-112; however, RTI-112 was still able to suppress cocaine administration at the ED50, suggesting a serotonergic mechanism was responsible for this.