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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 123/131I-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. 11C-HED and 18F-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.

SUBMITTER: Chen X

PROVIDER: S-EPMC7223405 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeA new PET radiotracer 18F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure-activity relationships (SARs) of NET-targeting radiotracers have rarely been performed.MethodsWithout changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of 18F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET.ResultsUsing non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer-NET interaction, whereby a T-shaped π-π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data.ConclusionThe SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors.

Project description:In vivo positron emission tomography (PET) imaging of the ?-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[11C]methylnipecotic acid confirmed the low brain uptake of that small and polar molecule. The common design approach to improve blood-brain barrier permeability of GAT-1 inhibitors is the attachment of a large lipophilic substituent. We selected an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer from a series recently reported by Wanner and coworkers. Nucleophilic aromatic substitution of an aryl chloride precursor with [18F]fluoride was used to prepare the desired candidate radiotracer ( R, E/ Z)-1-(2-((4-fluoro-2-(4-[18F]fluorobenzoyl)styryl)oxy)ethyl)piperidine-3-carboxylic acid (( R, E/ Z)-[18F]10). PET studies in rats showed no brain uptake, which was not altered by pretreatment of animals with the P-glycoprotein inhibitor cyclosporine A, indicating efflux by Pgp was not responsible. Subsequent PET imaging studies of ( R, E/ Z)-[18F]10 in rhesus monkey brain showed very low brain uptake. Finally, to test if the free carboxylic acid group was the likely cause of poor brain uptake, PET studies were done using the ethyl ester derivative of ( R, E/ Z)-[18F]10. Rapid and significant monkey brain uptake of the ester was observed, followed by a slow washout over 90 min. The blood-brain barrier permeability of the ester supports a hypothesis that the free acid function limits brain uptake of nipecotic acid-based GAT-1 radioligands, and future radiotracer efforts should investigate the use of carboxylic acid bioisosteres.

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

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