Abstract
1595
Objectives: The fluorine-18 norepinephrine transporter substrate N-[3-bromo-4-(3-[18F]fluoropropoxy)-benzyl]-guanidine ([18F]LMI1195, [18F]flubrobenguane) is under investigation for PET imaging of sympathetic innervation in patients with cardiomyopathies and other pathologies.1 A previous study reported on the clearance and metabolism of this radiotracer in healthy subjects and found some evidence for heterogeneity.2 Tracer handling in these respects have yet to be evaluated in those with altered sympathetic nervous system function.
Methods: Eight participants (ischemic cardiomyopathy n = 2; non-ischemic cardiomyopathy n = 2, post-traumatic stress disorder n = 4) underwent dynamic [18F]LMI1195 PET scans with blood sampling over the course of the 40-60 minute imaging session. Activity concentrations in whole blood and plasma filtrate were measured by gamma counting at several time points early and throughout the scan. The radioactive metabolites in plasma were separated from parent compound by column-switching HPLC3 or solid-phase extraction to assess tracer stability in vivo. Plasma protein binding was also tested by ultrafiltration using blood freshly drawn prior to tracer administration.
Results: The blood activity distribution peaked at approximately 1.40 plasma to whole blood ratio, and began to plateau at 0.56 ± 0.05, 10.2 ± 0.12 minutes post-injection across all imaging group cohorts. Parent fraction separations conducted by HPLC and SPE were highly consistent in parallel studies. By HPLC, polar metabolites eluted during the first 12 minutes of the analysis, whereas the parent [18F]LMI1195 compound eluted at 14 minutes. [18F]LMI1195 blood activity concentration peaked 1-2 minutes after administration and cleared rapidly to mean concentrations of 0.000832 ± 0.000344%, 0.000675 ± 0.000199%, 0.000384 ± 0.000261% injected dose per millilitre 5 minutes into the study, in ischemic, non-ischemic, and PTSD patients, respectively. The ischemic and non-ischemic cardiomyopathy patient data offered disparate metabolism profiles, with respective parent fractions of 29.5 ± 0.3% and 53.3 ± 12.2% at 30 minutes. Metabolism was found to be variable within the PTSD patient cohort at 20 minutes, and more consistently arrived at 24.0 ± 4.9% by 40-minutes. Plasma protein binding was also consistent across the three groups at 22.0 ± 1.8%.
Conclusions: These preliminary results suggest notable differences in the clearance and metabolic profiles of [18F]LMI1195 dependent on the given disease pathology. Radiotracer parent fraction can be equally measured by column-switching HPLC or SPE. These findings offer an important consideration for estimation of myocardial sympathetic nerve density using [18F]LMI1195 in patients suffering from cardiovascular disease. Support: Heart & Stroke Foundation of Canada/CANet ERLI (Rotstein) References: [1] Zelt, J. G. E. et al. J. Nucl. Cardiol. 2019, 26 (6), 2151-2153. [2] Sinusas, A. J. et al. J. Nucl. Med. 2014, 55 (9), 1445-1451. [3] Hilton, J. et al. Nucl. Med. Biol. 2000, 27 (6), 627-630.