Chemistry and Biology of Radiotracers That Target Changes in Sympathetic and Parasympathetic Nervous Systems in Heart Disease

Abstract

Following the discovery of the sympathetic and parasympathetic nervous system, numerous adrenoceptor drugs were radiolabeled and potent radioligands were prepared in order to image the β-adrenergic and the muscarinic systems. But the greatest effort has been in preparing noradrenaline analogs, such as norepinephrine, 11 C-metahydroxyephedrine, and 123 I-metaiodobenzylguanidine that measure cardiac sympathetic nerve varicosities. Given the technical and clinical challenges in designing and validating targeted adrenoceptor-binding radiotracers, namely the heavily weighted flow dependence and relatively low target-to-background ratio, both requiring complicated mathematic analysis, and the inability of targeted adrenoceptor radioligands to have an impact on clinical care of heart disease, the emphasis has been on radioligands monitoring the norepinephrine pathway. The chemistry and biology of such radiotracers, and the clinical and prognostic impact of these innervation imaging studies in patients with heart disease, are examined.

123I‐MIBG imaging for detection of anthracycline‐induced cardiomyopathy

“…This increase in cardiac sympathetic drive has potentially beneficial effects in early stages of HF, but is detrimental in the long run (Knuuti & Sipola, 2005). In the acute phase of HF, increased sympathetic activation functions to restore cardiac contractility and cardiac output (Eckelman & Dilsizian, 2015). However, chronic increases in cardiac sympathetic drive can result in reduced NA reuptake in presynaptic neurons (Caldwell et al, 2008;Christensen et al, 2014) although HF with conservation of neuronal NA reuptake capacity has also been reported (Meredith et al, 1993).…”

“…Evaluation of cardiac adrenergic function has several different applications in HF patients including assessment of prognosis Jacobson et al, 2010) and evaluation of treatment response (Yamazaki et al, 2001;Kasama et al, 2007). Due to the pivotal role of cardiac sympathetic activation in HF, several radiolabelled adrenoceptor drugs for cardiac radionuclide imaging have been developed (Eckelman & Dilsizian, 2015). Due to the pivotal role of cardiac sympathetic activation in HF, several radiolabelled adrenoceptor drugs for cardiac radionuclide imaging have been developed (Eckelman & Dilsizian, 2015).…”

“…Additionally, the hyperadrenergic state may result in reduced NA synthesis which in combination with the reduced neuronal reuptake results in intraneuronal NA depletion (Christensen et al, 2014). Postsynaptic effects of prolonged sympathetic hyperactivation include downregulation and desensitization of postsynaptic b-adrenergic receptors (Caldwell et al, 2008) and hence declining postsynaptic response to adrenergic stimulation with resulting adrenergic functional impairment and ensuing deterioration of cardiac function Eckelman & Dilsizian, 2015). Evaluation of cardiac adrenergic function has several different applications in HF patients including assessment of prognosis Jacobson et al, 2010) and evaluation of treatment response (Yamazaki et al, 2001;Kasama et al, 2007).…”

“…Furthermore, imaging of cardiac sympathetic innervation in HF can provide basic information regarding overall neuronal function and integrity which can be used in assessment of chemotherapy-related cardiotoxicity. Due to the pivotal role of cardiac sympathetic activation in HF, several radiolabelled adrenoceptor drugs for cardiac radionuclide imaging have been developed (Eckelman & Dilsizian, 2015). Although used for decades, especially in Europe and Japan, the recent US approval of 123 I-MIBG has increased the interest for this imaging modality (Gupta & Amanullah, 2014).…”

Principles of Molecular Targeting for Radionuclide Therapy

“…But for diagnostic radiotracers, it is clear that efflux of radioligand not specifically bound to the target in the tissue compartment must be rapid and efficient within the time frame of the radionuclide half-life. In cardiology, radioligands designed to measure changes in biochemical pathways are heavily weighted by distribution and require saturation studies in vivo to determine adrenoceptor density [17]. One example of a reversible ligand from neurochemistry studies is 3- [4-[(3-[ 18…”