The Impact of Ageing on [¹¹C]meta-Hydroxyephedrine Uptake in the Rat Heart

Objectives: An extensive body of evidence has reported on physiological age-related changes in autonomic nervous system function. The influence of ageing on myocardial sympathetic innervation remains to be fully understood. We aimed to elucidate the impact of physiological ageing on [¹¹C]meta-Hydroxyephedrine ([¹¹C]HED) uptake in the rat heart.

Methods: First, to confirm specific uptake via the neural norepinephrine transporter, the effect of specific activity on cardiac [¹¹C]HED uptake was evaluated: [¹¹C]HED was synthesized by N-methylation of (−)-metaraminol as the free base (radiochemical purity > 95%). [¹¹C]HED (48.7+/-9.7MBq, ranged 0.2-60.4μg/kg cold mass) was injected via tail vein in 14 healthy male Wistar Rats. Dynamic 23-frame PET images were obtained over 30 min. Time activity curves were generated for the blood input function and myocardial tissue. Cardiac [¹¹C]HED retention index (%/min) was calculated as myocardial tissue activity at 20-30 min divided by the integral of the blood activity curves. After confirming the specificity of [¹¹C]HED handling in the nerve terminal, the impact of ageing on myocardial [¹¹C]HED uptake was investigated longitudinally: PET studies at different ages (month (M) 2, 5, 11 and 15) were conducted by injecting of 55 MBq [¹¹C]HED (specific activity, 370-740 GBq/μmol) and the retention index (%/min) was assessed (n=7, respectively).

Results: [¹¹C]HED dynamic PET with different tracer specific activities showed rapid blood clearance and clear delineation of the myocardium in all animals. A dose-dependent reduction of cardiac [¹¹C]HED uptake was observed. The estimated retention index as a marker of norepinephrine function decreased at lower specific activity (higher amount of cold mass): Retention indices were 11.7, 11.7, 11.4, 11.7, 10.6, 10.9, 9.9, 8.8, 7.9 and 6.8 (%/min) for total injected cold masses (μg/kg) of 0.2, 0.4, 1, 1.5, 3, 4, 10, 17, 34 and 60, respectively. The EC50 value (95% CI) was 46.6 (32.3-67.1) μg/kg. This high affinity of [¹¹C]HED to the neural norepinephrine transporter triggered a subsequent study: In a longitudinal setting, the [¹¹C]HED retention index (%/min) decreased with increasing age (month 2: 8.9±2.1, M5: 9.2±1.09, M11: 7.9±1.64, M15: 6.3±1.1; M2 and M5 vs. M15, p<0.05, respectively).

Conclusions: We could observe specific uptake of [¹¹C]HED via the neural norepinephrine transport system in the rat heart. Second, the herein reported impact of physiological ageing on myocardial [¹¹C]HED uptake in rats is consistent with the generalized decrease of peripheral somatic nerve function in the ageing population. Research Support: This work was supported by the Competence Network of Heart Failure funded by the Integrated Research and Treatment Center (IFB) of the Federal Ministry of Education and Research (BMBF) and German Research Council (DFG grant HI 1789/3-3). This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 701983.

• Download figure
• Open in new tab
• Download powerpoint