[11C]HED PET

[11C]‑(–)‑m‑hydroxyephedrine ([11C]mHED, [11C]HED) is a widely used PET radiopharmaceutical for assessing cardiac sympathetic innervation (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, based on the structure of sympathomimetic drug norfenefrine. [11C]HED is not metabolized by MAO or COMT. [11C]HED is actively transported into presynaptic sympathetic nerve terminals by the noradrenaline transporter (NAT). Inside neurons, this radiopharmaceutical is taken up into noradrenaline storage vesicles by VMAT2 and its tissue concentration may represent a balance between continuous release and reuptake (DeGrado et al., 1993; Nomura et al., 2006).

Noradrenaline (norepinephrine) [C-11]HED
Noradrenaline, and [11C]HED

The uptake of [11C]HED by NATs is very rapid and may be flow-limited especially if perfusion is reduced in heart failure (Jang et al., 2013; Mu et al., 2020; Zelt et al., 2020).

A semiquantitative method, FUR, has been used to analyse [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).

Plasma metabolite fractions have been fitted with exponential function (Bernacki et al., 2016). In myocardial studies, with metabolite corrected arterial input, a compartmental model with spill-over correction for the right ventricular cavity can be applied to quantify 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. Separately assessed myocardial perfusion can be included in the model (Caldwell et al., 1998; Link et al., 2003).

In diagnostics of regional cardiac sympathetic denervation, static scans (starting 20 min after injection) are scaled to maximal uptake in myocardium, and scored based on a threshold value. With appropriate software, excellent inter-rater reliability can be achieved (Wang et al., 2021).

Analysis method in TPC

FUR (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 calculation can be done in Carimas™ or with CLI programs regfur for regional TTAC data and imgfur for image data.

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.


See also:


Literature

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. doi: 10.1016/0735-1097(93)90553-d.

Caldwell JH, Kroll K, Li Z, Seymour K, Link JM, Krohn KA. Quantitation of presynapctic cardiac sympathetic function with carbon-11-meta-hydroxyephedrine. J Nucl Med. 1998; 39: 1327-1334. PMID: 9708501.

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. PMID: 8326386.

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. doi: 10.1186/s13550-014-0052-4.

Knuuti J, Sipola P. Is it time for cardiac innervation imaging? Q J Nucl Med Mol Imaging 2005; 49: 97-105. PMID: 15724139.

Lautamäki R, Tipre D, Bengel FM. Cardiac sympathetic neuronal imaging using PET. Eur J Nucl Med Mol Imaging 2007; 34(Suppl 1): S74-S85. doi: s00259-007-0442-1.

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. doi: 10.3389/fphys.2012.00006.

Noordzij W, Slart RH. PET imaging of the autonomic myocardial function: methods and interpretation. Clin Transl Imaging 2015; 3(5): 365-372. doi: 10.1007/s40336-015-0139-6.

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. doi: 10.1007/s002590000449.

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. PMID: 12050322.

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. PMID: 16954558.

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. doi: 10.1016/j.nucmedbio.2012.11.014.

Vesalainen RK, Pietilä M, Tahvanainen KU, 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. doi: 10.1016/s0002-9149(99)00379-3.



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Updated at: 2022-02-17
Created at: 2014-05-20
Written by: Vesa Oikonen