[C]mHED PET follows a two-tissue compartment model in mouse myocardium with norepinephrine transporter (NET)-dependent uptake, while [F]LMI1195 uptake is NET-independent.

Purpose: Clinical positron emission tomography (PET) imaging of the presynaptic norepinephrine transporter (NET) function provides valuable diagnostic information on sympathetic outflow and neuronal status. As data on the NET-targeting PET tracers [C]meta-hydroxyephedrine ([C]mHED) and [F]LMI1195 ([F]flubrobenguane) in murine experimental models are scarce or lacking, we performed a detailed characterization of their myocardial uptake pattern and investigated [C]mHED uptake by kinetic modelling.

Methods: [C]mHED and [F]LMI1195 accumulation in the heart was studied by PET/CT in FVB/N mice. To test for specific uptake by NET, desipramine, a selective NET inhibitor, was administered by intraperitoneal injection. [C]mHED kinetic modelling with input function from an arteriovenous shunt was performed in three mice.

Results: Both tracers accumulated in the mouse myocardium; however, only [C]mHED uptake was significantly reduced by excess amount of desipramine. Myocardial [C]mHED uptake was half-saturated at 88.3 nmol/kg of combined mHED and metaraminol residual. After [C]mHED injection, a radiometabolite was detected in plasma and urine, but not in the myocardium. [C]mHED kinetics followed serial two-tissue compartment models with desipramine-sensitive K.

Conclusion: PET with [C]mHED but not [F]LMI1195 provides information on NET function in the mouse heart. [C]mHED PET is dose-independent in the mouse myocardium at < 10 nmol/kg of combined mHED and metaraminol. [C]mHED kinetics followed serial two-tissue compartment models with K representing NET transport. Myocardial [C]mHED uptake obtained from PET images may be used to assess cardiac sympathetic integrity in mouse models of cardiovascular disease.