European Nuclear Medicine Guide
[123I]iobenguane, also known as meta-[123I]iodobenzylguanidine (mIBG).
[11C]-hydroxyephedrine,
[11C]-epinephrine,
[11C]-phenylephrine (PHEN)
[18F]-meta-fluorobenzylguanidine
[18F]-hydroxyphenetylguanidine
Tracers suitable for SPECT scan:
Norepinephrine (NE), a neurotransmitter of the sympathetic system, is synthesized from the amino acid tyrosine and stored in high concentration in the presynaptic vesicles. Upon stimulation, NE is released into the synaptic space, binding to postsynaptic receptors β1 and β2 and promoting a sympathetic response that is stopped by a postsynaptic re-uptake mechanism (via pathways uptake-1 and uptake-2) that takes NE back into the presynaptic terminal.
Guanethidine is a false neurotransmitter analogue of NE that can be radiolabelled with iodine, most commonly [123I]. The molecular structure of mIBG (Metaiodobenzylguanidine) is similar to that of NE and presents the same uptake and storage mechanism, but, in contrast, it is not catabolized by monoamine oxidase or catechol-O-methyltransferase. Subsequently, it is retained and localized in the myocardial sympathetic nerve terminal endings [41].
Tracers suitable for PET scan:
Positron emission tomography (PET) imaging allows for quantification of global and regional abnormalities in cardiac sympathetic activity based on tracer activity concentrations (Bq/mL) in the myocardium and blood pool in dynamic datasets using a retention analysis. The superior intrinsic spatio-temporal resolution and attenuation is well documented [42,43].
PET uses short-lived [11C]-labelled tracers or longer-lived [18F]-labelled tracers that differ in their affinity to the NE transporter, vesicular storage and metabolism and in their flow dependency, leading to distinct differences in their kinetics and specificity.
For example, [11C]-hydroxyephedrine is a lipophilic, metabolically resistant catecholamine analogue that reflects activity of the sarcolemmal norepinephrine transporter (uptake-1) and can be used to assess the contribution of neuronal transport, while [11C]-epinephrine is avidly taken up by uptake-1 but then requires vesicular storage within presynaptic neurons for protection from metabolic degradation and can be used to assess vesicular storage. [11C]-phenylephrine (PHEN), on the other hand, is another synthetic catecholamine which, following uptake and storage, leaks from vesicles even under physiological conditions and is then subjected to intraneuronal enzymatic degradation by monoaminoxidase [44]. These tracers have been successfully and safely applied to image myocardial sympathetic nerve terminals, but they have never been combined in the same imaging protocol in humans, a combination that could provide mechanistic information about differential effects of disease on anatomical nerve density, as well as about functional changes in cellular catecholamine uptake, storage and metabolism [42]. The major limitation of [11C]-labelled tracers is their short half-life, which requires an on-site cyclotron and limits their widespread use in the clinical setting. More recently, [18F]-labelled tracers have been introduced. [18F]-meta-fluorobenzylguanidine has similar kinetics to 123I-mIBG and was well tolerated in a phase 1 clinical trial. However, for the aforementioned reasons, the available clinically relevant data mainly pertain to SPECT scans.
Risk stratification in patients with congestive heart failure (CHF) with NYHA class II or III and LVEF ≤35% and support in the selection of patients for implantable cardiac devices (ICD): mIBG H/M ratio ≥1.6 has been shown to identify patients with low (1- to 2-year) mortality risk [45,46].
Arrhythmias and sudden cardiac death (SCD) prevention to assess the potential clinical benefits of ICD implantation.
Ventricular arrhythmias risk assessment in ischaemic heart failure [47].
(application without dedicated indication according to registered prescribing information).
Differential diagnosis between Parkinson’s disease (PD) and other parkinsonian syndromes (MSA, PSP and CBD), as well as between dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) (Off-label use in some European countries) [48].
Early-stage assessment of cardiac amyloidosis [49,50]
Pregnancy.
Breastfeeding: When 123I-mIBG is used, breastfeeding should be discontinued for at least 24 h after injection [51]. Breast milk may be collected and stored beforehand, in order to be provided to the infant during the interruption period.
Plasma clearance of [123I]-mIBG is reduced in patients with renal insufficiency. MIBG is not cleared by dialysis [51,52]
Patients with known hypersensitivity to mIBG or mIBG sulphate [51,52]
Many drugs modify the uptake and storage of mIBG and should be discontinued: tricyclic antidepressants, sympathomimetics, antipsychotics, antihypertensive agents (reserpine, calcium channel blockers, labetalol), tramadol, opioids, cocaine [52].
It is also important that patients stop eating food that may interfere with mIBG uptake, such as catecholamine-like compounds (e.g. chocolate and blue cheese) [52].
Unintentional radioactive iodine uptake in the thyroid must be avoided by administration for 2–3 days of sodium or potassium iodide (100–150 mg per day) or sodium or potassium perchlorate (200–400 mg per day), starting at least 30 minutes before administration of the radiopharmaceutical.
123I physical half-life is 13.2 hours.
The appropriate dosage of mIBG has not been definitively established. For planar images, several published studies suggest an activity of 111–185 MBq by slow (over 1 to 2 min) secure peripheral intravenous injection flushed with saline to avoid rare (<1%) adverse events (dizziness, rash, pruritus, flushing and injection site haemorrhage). In adult patients with systolic heart failure, a dose of 370 MBq ±10% may be appropriate in order to obtain single-photon emission computerized tomographic (SPECT) images [46,53].
More recently, the introduction of dedicated cardiac cameras equipped with solid-state cadmium–zinc–telluride (CZT) detectors has offered the advantage of reduced injected activities thanks to their increased count sensitivity, as well as the ability to perform dual-isotope imaging with perfusion tracers to assess innervation and myocardial viability at the same time [42].
The effective radiation dose is 0.013 mSv/MBq, with an increased radiation dose from CT in the case of SPECT/CT protocols (CT volume dose index: 3–5 mGy depending on acquisition parameters) [54]. Organs with the highest absorbed dose per unit activity administered are the liver (0.067 mGy/MBq), bladder, gallbladder, spleen, heart, and adrenals: ample hydration should be encouraged as well as frequent urinary voiding in the first 48 hours following administration [46, 60].
Caveat
“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
Planar and SPECT images are routinely obtained 15 minutes (early) and 4 hours (delayed) after mIBG administration, using a low-energy high-resolution (LEHR) parallel hole collimator and an energy window of 159 keV±20% [52].
On planar images, acquired for 10 min in the anterior view and stored in a 128×128 or 256×256 matrix, both qualitative and quantitative analysis are performed. Qualitative evaluation involves the location, pattern and intensity of cardiac mIBG uptake to guide quantitative analysis using the heart/mediastinum ratio (H/M), which reflects the integrity of the cardiac sympathetic nerves.
The H/M is calculated by dividing the mean counts per pixel in the heart by the mean counts per pixel in the mediastinum, obtained by drawing regions of interest (ROI) on the anterior planar image over the heart, including or not including the cavity, and over the upper mediastinum (avoiding the thyroid gland) [52].
Another quantitative index is the myocardial washout rate (WR), calculated as the percentage decrease in myocardial mIBG counts over the time difference from early to delayed images. This is an important measure of cardiac sympathetic innervation, reflecting turnover of catecholamines and thus the degree of sympathetic drive [41].
Normal values for late H/M ratio and WR vary in relation to age (inversely for the late H/M ratio, directly for the WR), image acquisition protocols and clinical indication. Improvement in the standardization of cardiac mIBG imaging protocols would contribute to increased clinical applicability of this procedure [52].
SPECT images, stored in a 64×64 matrix, and derived polar maps (bull’s eye display) facilitate assessment of the presence, extent and location of sympathetic abnormalities. All three image planes (short axis, horizontal long axis and vertical long axis) should be inspected of both late and early images displayed on a continuous colour scale, preferably the same as that employed for myocardial perfusion imaging [52].
Patients with CHF present reduced cardiac mIBG uptake, and among these patients, those with the lowest uptake tend to have the poorest prognosis [52]. Furthermore, some studies have also revealed that abnormalities in cardiac mIBG uptake may be predictive of increased risk of ventricular arrhythmia and sudden cardiac death, and thereby may guide the use of ICD. Myocardial scar represents an important substrate for the occurrence of potentially fatal ventricular arrhythmias, and patients with LVEF <30%–35% present an increased risk for sudden cardiac death, requiring ICD implantation to reduce the risk [41].
The largest published prospective study, ADMIRE-HF [45], has provided validation of the independent prognostic value of cardiac mIBG imaging in the assessment of patients with heart failure. A total of 961 patients with CHF, NYHA class II or III and LVEF ≤35% were included. All patients underwent mIBG myocardial imaging and were then followed up for up to 2 years.
The cardiac event risk was significantly lower for subjects with H/M ≥1.60, with a hazard ratio of 0.40 (97.5% CI: 0.25 to 0.64; p < 0.001); the two-year event rate was 15% for H/M ≥ 1.60 and 37% for H/M <1.60. Hazard ratios for individual event categories were as follows: HF progression, 0.49 (p = 0.002); arrhythmic events, 0.37 (p = 0.02); and cardiac death, 0.14 (p =0.006). Combined “arrhythmic” events (self-limited ventricular tachycardia, resuscitated cardiac arrest, appropriate ICD discharges, sudden cardiac death) were more common in subjects with H/M <1.60 (p < 0.01), and the highest prevalence of arrhythmic events was in the H/M range of 1.30 to 1.39 [45].
Standardization of mIBG cardiac sympathetic imaging should contribute to increasing its clinical applicability and its integration into current nuclear cardiology practice [52].
In the field of neurology, [123I]-mIBG cardiac uptake is reduced in around 80–90% of patients with Lewy body diseases (PD and DLB) but preserved in other parkinsonian syndromes (MSA, PSP) and Alzheimer’s disease, allowing differential diagnosis [48]. Substantial numbers of patients have already been imaged, and a large meta-analysis of 2680 subjects identified a H/M threshold of 1.77 to distinguish PD and DLB from healthy controls and patients with other neurodegenerative diseases [55]. Despite these results, clinical trials and procedural guidelines for acquisition, reading and reporting are required to confirm mIBG as an imaging tool to determine cardiac sympathetic denervation in this clinical setting [56].
In the case of ischaemic heart failure, mIBG could be a diagnostic tool for risk assessment of lethal ventricular arrhythmic events (ArEs) and could guide clinical decisions on ICD implantation [47].
Clinical evidence has demonstrated that regions of innervation/perfusion mismatch (mIBG/[99Tc]-tetrofosmin or sestamibi) predispose to arrhythmias: cardiac regions with denervated but perfused viable myocardium may exhibit denervation supersensitivity and predispose to potentially lethal arrhythmias [41]. The presence of areas of viable but denervated myocardium located nearby scarred regions, identified by innervation/perfusion mismatch with SPECT (mIBG/[99Tc]-tetrofosmin or sestamibi), is a potential source of ventricular arrhythmias and, as a consequence, an ideal site for targeted therapeutic intervention, such as endocavitary ablations [42,57]. Further prospective multicentre studies are required to explore the relationship between ArEs and regional innervation defects and innervation/perfusion mismatches.