Quantification of sympathetic nerve density with [11C]HED
[11C]‑(–)‑m‑hydroxyephedrine ([11C]HED) is a widely used PET tracer for cardiac neuronal imaging (Knuuti & Sipola, 2005; Lautamäki et al., 2007). [11C]HED can also be used to measure the sympathetic nerve density in other tissues, such as brown adipose tissue (Muzik et al., 2017). [11C]HED can be used in imaging of neuroblastomas (Shulkin et al. 1996) and pheochromocytomas (Trampal et al. 2004).
[11C]HED is a catecholamine analogue, and it is actively transported into presynaptic sympathetic nerve terminals by the norepinephrine transporter (NET). Inside neurons, tracer is taken up into norepinephrine storage vesicles by VMAT2. [11C]HED is not metabolized by MAO or COMT.
The uptake of [11C]HED is very rapid and flow-limited (Jang et al., 2013). Retention is also dependent on the NET density of the heart (Raffel et al., 2006), with a balance between continuous release and reuptake (DeGrado et al., 1993). A semiquantitative method, FUR, has been used to analyze [11C]HED PET data, although it and SUV show a non-linear relationship with the distribution volume. FUR is traditionally called Retention Index (RI) in analysis of [11C]HED data. The flow-limited neuronal uptake causes the FUR to be insensitive to substantial nerve losses as long as myocardial perfusion is not reduced (Jang et al., 2013).
With metabolite corrected arterial input a compartmental model with spill-over correction for the right ventricular cavity can be applied to quantitate the distribution volume (Harms et al., 2014). Although the reversible two-tissue compartmental model provided better fits, Harms et al (2014) proposed using one-tissue compartmental model instead, because of its robustness.
Analysis method in TPCFUR (retention index, RI) is calculated as the myocardial activity at a late time (30–40 min p.i.) divided by the integral of metabolite corrected arterial blood activity curve, derived from a small ROI drawn in the LV cavity, and parent tracer fractions that can be measured from separate venous blood samples collected during the PET study (Vesalainen et al., 1999). Usually, blood TAC is not corrected for metabolites.
FUR can be corrected for blood-flow -related variability by dividing it by regional MBF (Jayachandran et al., 2002; Pietilä et al., 2002):
For full quantification a reversible one-tissue compartmental model with spillover correction from RV should be considered.
Allman, KC, Stevens MJ, Wieland DM, Hutchins GD, Wolfe ER Jr, Greene DA, Schwaiger M. Noninvasive assessment of cardiac diabetic neuropathy by carbon-11 hydroxyepheprine and positron emission tomography. J Am Coll Cardiol. 1993; 22: 1425-1432.
Caldwell JH, Kroll K, Li Z, Seymour K, Link JM, Krohn KA. Qunatitation of presynapctic cardiac sympathetic function with carbon-11-meta-hydroxyephedrine. J Nucl Med. 1998; 39: 1327-1334.
DeGrado TR, Hutchins GD, Toorongian SA, Wieland DM, Schwaiger M. Myocardial kinetics of carbon-11-meta-hydroxyephedrine: retention mechanisms and effects of norepinephrine. J Nucl Med. 1993; 34(8): 1287-1293.
Harms HJ, de Haan S, Knaapen P, Allaart CP, Rijnierse MT, Schuit RC, Windhorst AD, Lammertsma AA, Huisman MC, Lubberink M. Quantification of [11C]-meta-hydroxyephepride uptake in human myocardium. EJNMMI Res. 2014; 4:52.
Jang KS, Jung Y-W, Koeppe RA, Sherman PS, Quesada CA, Raffel DM. 4-[18F]fluoro-m-hydroxyphenethylguanidine: a radiopharmaceutical for quantifying regional cardiac sympathetic nerve density with positron emission tomography. J Med Chem. 2013; 56: 7312-7323.
Jayachandran JV, Sih HJ, Winkle W, Zipes DP, Hutchins GD, Olgin JE. Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. Circulation 2000; 101(10): 1185-1191.
Knuuti J, Sipola P. Is it time for cardiac innervation imaging? Q J Nucl Med Mol Imaging 2005; 49: 97-105.
Lautamäki R, Tipre D, Bengel FM. Cardiac sympathetic neuronal imaging using PET. Eur J Nucl Med Mol Imaging 2007; 34: S74-S85.
Mäki MT, Koskenvuo JW, Ukkonen H, Saraste A, Tuunanen H, Pietilä M, Nesterov SV, Aalto V, Airaksinen KEJ, Pärkkä JP, Lautamäki R, Kervinen K, Miettinen JA, Mäkikallio TH, Nielemä M, Säily M, Koistinen E-R, Savolainen E-R, Ylitalo K, Huikuri HV, Knuuti J. Cardiac function, perfusion, metabolism, and innervation following autologous stem cell therapy for acute ST-elevation myocardial infarction. A FINCELL-INSIGHT sub-study with PET and MRI. Front Physiol. 2012; 3: 6.
Pietilä M, Malminiemi K, Vesalainen R, Jartti T, Teräs M, Någren K, Lehikoinen P, Voipio-Pulkki LM. Exercise training in chronic heart failure: beneficial effects on cardiac 11C-hydroxyephedrine PET, autonomic nervous control, and ventricular repolarization. J Nucl Med. 2002; 43(6): 773-779.
Pietilä M, Malminiemi K, Ukkonen H, Saraste M, Någren K, Lehikoinen P, Voipio-Pulkki LM. Reduced myocardial carbon-11 hydroxyephedrine retention is associated with poor prognosis in chronic heart failure. Eur J Nucl Med. 2001; 28(3): 373-376.
Raffel DM, Chen W, Jung Y-W, Jang KS, Gu G, Cozzi NV. Radiotracers for cardiac sympathetic innervation: transport kinetics and binding affinities for the human norepinephrine transporter. Nucl Med Biol. 2013; 40: 331-337.
Raffel DM, Chen W, Sherman PS, Gildersleeve DL, Jung YW. Dependence of cardiac 11C-meta-hydroxyephedrine retention on norepinephrine transporter density. J Nucl Med. 2006; 47(9): 1490-1496.
Vesalainen RK, Pietilä M, Tahvanainen KUO, Jartti T, Teräs M, Någren K, Lehikoinen P, Huupponen R, Ukkonen H, Saraste M, Knuuti J, Voipio-Pulkki L-M. Cardiac positron emission tomography imaging with [11C]hydroxyephedrine, a specific tracer for sympathetic nerve endings, and its functional correlates in congestive heart failure. Am J Cardiol. 1999; 84: 568-574.
Updated at: 2018-12-12
Created at: 2014-05-20
Written by: Vesa Oikonen