Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

Abstract

The norepinephrine transporter (NET) is a major target for the evaluation of the cardiac sympathetic nerve system in patients with heart failure and Parkinson's disease. It is also used in the therapeutic applications against certain types of neuroendocrine tumors, as exemplified by the clinically used 123/131 I-MIBG as theranostic single-photon emission computed tomography (SPECT) agent. With the development of more advanced positron emission tomography (PET) technology, more radiotracers targeting NET have been reported, with superior temporal and spatial resolutions, along with the possibility of functional and kinetic analysis. More recently, fluorine-18-labelled NET tracers have drawn increasing attentions from researchers, due to their longer radiological half-life relative to carbon-11 (110 min vs. 20 min), reduced dependence on on-site cyclotrons, and flexibility in the design of novel tracer structures. In the heart, certain NET tracers provide integral diagnostic information on sympathetic innervation and the nerve status. In the central nervous system, such radiotracers can reveal NET distribution and density in pathological conditions. Most radiotracers targeting cardiac NET-function for the cardiac application consistent of derivatives of either norepinephrine or MIBG with its benzylguanidine core structure, e.g. 11 C-HED and 18 F-LMI1195. In contrast, all NET tracers used in central nervous system applications are derived from clinically used antidepressants. Lastly, possible applications of NET as selective tracers over organic cation transporters (OCTs) in the kidneys and other organs controlled by sympathetic nervous system will also be discussed.

[11C]mHED PET follows a two-tissue compartment model in mouse myocardium with norepinephrine transporter (NET)-dependent uptake, while [18F]LMI1195 uptake is NET-independent

“…In rats, myocardial uptake was assigned to the extra-neuronal "uptake-2" mechanism. The suspected transporter protein(s) mediating "uptake-2" is/are also present in the mouse myocardium [7,24]. We now extend these findings by demonstrating that [ 18 F]LMI1195 is accumulating in the mouse myocardium, but its uptake is not related to NET function, in agreement with the findings in rats.…”

“…The development of radioligands targeting the presynaptic norepinephrine transporter (NET, "uptake-1", SLC6A2), such as the benzylguanidine analogue [ 123 I] meta -iodobenzylguanidine ([ 123 I]mIBG) for single-photon emission computed tomography (SPECT) and the norfenefrine analogue [ 11 C]meta-hydroxyephedrine ([ 11 C]mHED, [ 11 C]HED) for positron emission tomography (PET) has enabled the non-invasive assessment of the neurohumoral axis [ 7 ]. However, in clinical imaging, [ 123 I]mIBG is limited by the moderate resolution of SPECT.…”

Nuclear Medicine Imaging in Neuroblastoma: Current Status and New Developments

“…In recent years, many other benzylguanidine analogues have been developed [112]. 18 F-labeled fluoropropylbenzylguanidine (FPBG) PET-CT detected one extra (histologically confirmed) metastatic bone lesion compared to [ 123 I]mIBG scintigraphy in a case report of a neuroblastoma patient [113].…”

PET Radiotracers for CNS-Adrenergic Receptors: Developments and Perspectives

“…Among the three subtypes, α2A-ARs are the most abundant in the brain and localized in locus coeruleus, midbrain, hippocampus, hypothalamus, amygdala, cerebral cortex and brain stem. The α2B-ARs are located in thalamus and hypothalamus and α2C-ARs in cortex, hippocampus, olfactory tubercle and basal ganglia [ 51 , 52 , 53 ]. In the mouse brain, ~90% of α2-ARs are α2A-ARs and ~10% are α2C-ARs [ 30 , 31 , 32 , 82 ].…”

“…Various C-11 and F-18 radiotracers of NET-selective anti-depressants (e.g., reboxetine) were examined using PET to monitor the function of noradrenergic system in CNS. Radiotracers, for example, ( S,S )-[ 11 C] O -methyl-reboxetine ([ 11 C]MRB) and [ 18 F]FMeNER-D 2 , were shown to exhibit desirable in vivo properties and their regional distribution in the brain is consistent with known distribution of NET in preclinical/clinical settings [ 51 , 52 , 53 , 54 ]. These radiotracers have been employed to monitor NET availability in different related diseases, including obesity, major depressive disorder, and Parkinson’s disease.…”