ABSTRACT Purpose In the human brain endogenous dopamine release is commonly assessed by the PET competition model. Although thoroughly validated, cognitive processing yields low signal changes and the assessment of several task conditions requires repeated scanning. Using the framework of functional PET imaging we introduce a novel approach which leverages the incorporation of the radioligand 6-[ 18 F]FDOPA into the dynamic fast-acting regulation of the corresponding enzyme activities by neuronal firing and neurotransmitter release. We demonstrate the feasibility of the approach by the assessment of widely described sex differences in dopamine neurotransmission. Methods Reward and punishment processing was behaviorally investigated in 36 healthy participants, where 16 underwent fPET and fMRI while performing the monetary incentive delay task. 6-[ 18 F]FDOPA was applied as bolus+infusion during a single 50 min PET acquisition. Task-specific changes in dopamine synthesis were identified with the general linear model and quantified with the Gjedde-Patlak plot. Results Monetary gain induced 78% increase in nucleus accumbens dopamine synthesis vs. 49% for loss in men. Interestingly, the opposite was discovered in women (gain: 51%, loss: 78%). Behavioral modeling revealed direct associations of task-specific dopamine synthesis with reward sensitivity in men (rho = −0.7) and with punishment sensitivity in women (rho = 0.89). As expected, fMRI showed robust task-specific neuronal activation but no sex difference. Conclusions Our findings provide a dopaminergic basis for well-known behavioral differences in reward and punishment processing between women and men. This has important implications in psychiatric conditions showing sex-specific prevalence rates, altered reward processing and dopamine signaling. The high temporal resolution and pronounced magnitude of task-specific changes make fPET a promising tool to investigate functional neurotransmitter dynamics during cognitive or emotional processing in various brain disorders.

Functional dynamics of dopamine synthesis during monetary reward and punishment processing