Radiotracers for cardiac sympathetic innervation: Transport kinetics and binding affinities for the human norepinephrine transporter

Raffel, David M.; Chen, Wei; Jung, Y; Jang, Keum-Seong; Gu, Guie; Cozzi, Nicholas V.

doi:10.1016/j.nucmedbio.2012.11.014

Cited by 22 publications

(18 citation statements)

References 18 publications

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“…Although a number of studies evaluating the potential usefulness of [ 124 I]MIBG have appeared [7–11], as noted by others [12, 13], 124 I is not an ideal radionuclide for PET. MIBG analogues labeled with other positron emitters such as 76 Br and 11 C also have been reported [14, 15]. Bromine-76 also has a relatively long half-life and is not readily available; on the other hand, the half-life of 11 C is so short that radiochemical synthesis of 11 C-labeled compounds can often be challenging.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

Vaidyanathan

McDougald

Koumarianou

et al. 2015

Nuclear Medicine and Biology

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Introduction Radioiodinated meta-iodobenzylguanidine (MIBG), a norepinephrine transporter (NET) substrate, has been extensively used as an imaging agent to study the pathophysiology of the heart and for the diagnosis and treatment of neuroendocrine tumors. The goal of this study was to develop an 18F-labeled analogue of MIBG that like MIBG itself could be synthesized in a single radiochemical step. Towards this end, we designed 4-fluoropropoxy-3-iodobenzylguanidine (FPOIBG). Methods Standards of FPOIBG and 4-fluoropropoxy-3-bromobenzylguanidine (FPOBBG) as well as their tosylate precursors for labeling with 18F, and a tin precursor for the preparation of radioiodinated FPOIBG were synthesized. Radiolabeled derivatives were synthesized by nucleophilic substitution and electrophilic iododestannylation from the corresponding precursors. Labeled compounds were evaluated for NET transporter recognition in in vitro assays using three NET-expressing cell lines and in biodistribution experiments in normal mice, with all studies performed in a paired-label format. Competitive inhibition of [125I]MIBG uptake by unlabeled benzylguanidine compounds was performed in UVW-NAT cell line to determine IC50 values. Results [18F]FPOIBG was synthesized from the corresponding tosylate precursor in 5.2 ± 0.5% (n = 6) overall radiochemical yields starting with aqueous fluoride in about 105 min. In a paired-label in vitro assay, the uptake of [18F]FPOIBG at 2 h was 10.2 ± 1.5%, 39.6 ± 13.4%, and 13.3 ± 2.5%, in NET-expressing SK-N-SH, UVW-NAT, and SK-N-BE(2c) cells, respectively, while these values for [125I]MIBG were 57.3 ± 8.1%, 82.7 ± 8.9%, and 66.3 ± 3.6%. The specificity of uptake of both tracers was demonstrated by blocking with desipramine. The 125I-labeled congener of FPOIBG gave similar results. On the other hand, [18F]FPOBBG, a compound recently reported in the literature, demonstrated much higher uptake, albeit less than that of co-incubated [125I]MIBG. IC50 values for FPOIBG were higher than that obtained for MIBG and FPOBBG. Unlike the case with [18F]FPOBBG, the heart uptake [18F]FPOIBG in normal mice was significantly lower than that of MIBG. Conclusion Although [18F]FPOIBG does not appear to warrant further consideration as an 18F-labeled MIBG analogue, analogues wherein the iodine in it is replaced with a chlorine, fluorine or hydrogen might be worth pursuing. Advances in knowledge and implications for patient care An 18F-labeled analogue of the well-known radiopharmaceutical MIBG could have significant impact, potentially improving imaging of NET related disease in cardiology and in the imaging of neuroendocrine tumors. Although 18F-labeled analogues of MIBG have been reported including LMI1195, we undertook this work hypothesizing that based on its greater structural similarity to MIBG, FPOIBG might be a better analogue than LMI1195.

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Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

Vaidyanathan

McDougald

Koumarianou

et al. 2015

Nuclear Medicine and Biology

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“…Hence, while it is not possible to replay the evolutionary tape, it is entirely reasonable that many of the several hundred human uptake transporters [68] were in fact selected, at least in part, precisely to transport exogenous secondary metabolites. Indeed, mammalian transporters are well known for their ability to transport many exogenous natural product drugs, e.g., SLCO family members for penicillins [178; 179], cephalosporins [180; 181], tetracycline [182], caffeine, theobromine and theophylline [183] and digoxin [184], SLC22 for berberine [185] and protoberberines [186], morphine [187], erythromycin [188] and theophylline [188], SLC15 for penicillins and cephalosporins [189; 190], SLC6 family (norepinephrine transporters) [191] for ephedrine derivatives [192], and SLC36 for arecaidine (an active constituent of the Areca nut, often wrongly referred to as the betel nut) [193].…”

Section: Natural Products That Are Nutrients or Bioactive Drugs Must mentioning

confidence: 99%

Consensus rank orderings of molecular fingerprints illustrate the ‘most genuine’ similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

O’Hagan

Kell

2017

Preprint

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We compare several molecular fingerprint encodings for marketed, small molecule drugs, and assess how their rank order varies with the fingerprint in terms of the Tanimoto similarity to the most similar endogenous human metabolite as taken from Recon2. For the great majority of drugs, the rank order varies very greatly depending on the encoding used, and also somewhat when the Tanimoto similarity (TS) is replaced by the Tversky similarity. However, for a subset of such drugs, amounting to some 10% of the set and a Tanimoto similarity of ~0.8 or greater, the similarity coefficient is relatively robust to the encoding used. This leads to a metric that, while arbitrary, suggests that a Tanimoto similarity of 0.75-0.8 or greater genuinely does imply a considerable structural similarity of two molecules in the drug-endogenite space. Although comparatively few (<10% of) marketed drugs are, in this sense, robustly similar to an endogenite, there is often at least one encoding with which they are genuinely similar (e.g. TS > 0.75). This is referred to as the Take Your Pick Improved Cheminformatic Analytical Likeness or TYPICAL encoding, and on this basis some 66% of drugs are within a TS of 0.75 to an endogenite.We next explicitly recognise that natural evolution will have selected for the ability to transport dietary substances, including plant, animal and microbial 'secondary' metabolites, that are of benefit to the host. These should also be explored in terms of their closeness to marketed drugs. We thus compared the TS of marketed drugs with the contents of various databases of natural products. When this is done, we find that some 80% of marketed drugs are within a TS of 0.7 to a natural product, even using just the MACCS encoding. For patterned and TYPICAL encodings, 80% and 98% of drugs are within a TS of 0.8 to (an endogenite or) an exogenous natural product. This implies strongly that it is these exogeneous (dietary and medicinal) natural products that are more to be seen as the 'natural' substrates of drug transporters (as is recognised, for instance, for the solute carrier SLC22A4 and ergothioneine). This novel analysis casts an entirely different light on the kinds of natural molecules that are to be seen as most like marketed drugs, and hence potential transporter substrates, and further suggests that a renewed exploitation of natural products as drug scaffolds would be amply rewarded.

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“…[ 11 C]-Meta-hydroxyephedrine (HED) has been well characterized in cellular [12•], animal [13], and human [14] studies and is the most routinely used PET imaging agent for SNS nerve activity. [ 11 C]-HED is a metabolically resistant analog of NE.…”

Section: Tracers Of Sns Presynaptic Nerve Activitymentioning

confidence: 99%

“…Raffel has reported high binding affinity for human NET ( K i = 68.4 µM [12•]) similar to NE, while others have shown high specificity for myocardial uptake-1 (~90%) and vesicular transport (95%) [20]. Notably, [ 11 C]-EPI retention in the myocardium is not influenced by continual reuptake at the presynaptic cleft as is [ 11 C]-HED [13].…”

Section: Tracers Of Sns Presynaptic Nerve Activitymentioning

confidence: 99%

“…Dopamine is an endogenous neurotransmitter that has a high binding affinity ( K i = 8.1 (µ.M) and transport kinetics ( K m = 0.24 µ.M) to human NET [12•]. Dopamine is the substrate for VMAT vesicular packing and converts to NE within the presynaptic neuron, and is susceptible to intra- and extra-neuronal metabolism.…”

Section: Tracers Of Sns Presynaptic Nerve Activitymentioning

confidence: 99%

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Recent Advances and Clinical Applications of PET Cardiac Autonomic Nervous System Imaging

Boutagy

Sinusas

2017

Curr Cardiol Rep

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Purpose of Review The purpose of this review was to summarize current advances in positron emission tomography (PET) cardiac autonomic nervous system (ANS) imaging, with a specific focus on clinical applications of novel and established tracers. Recent Findings [11C]-Meta-hydroxyephedrine (HED) has provided useful information in evaluation of normal and pathological cardiovascular function. Recently, [11C]-HED PET imaging was able to predict lethal arrhythmias, sudden cardiac death (SCD), and all-cause mortality in heart failure patients with reduced ejection fraction (HFrEF). In addition, initial [11C]-HED PET imaging studies have shown the potential of this agent in elucidating the relationship between impaired cardiac sympathetic nervous system (SNS) innervation and the severity of diastolic dysfunction in HF patients with preserved ejection fraction (HFpEF) and in predicting the response to cardiac resynchronization therapy (CRT) in HFrEF patients. Longer half-life 18F-labeled presynaptic SNS tracers (e.g., [18F]-LMI1195) have been developed to facilitate clinical imaging, although no PET radiotracers that target the ANS have gained wide clinical use in the cardiovascular system. Although the use of parasympathetic nervous system radiotracers in cardiac imaging is limited, the novel tracer, [11C]-donepezil, has shown potential utility in initial studies. Summary Many ANS radioligands have been synthesized for PET cardiac imaging, but to date, the most clinically relevant PET tracer has been [11C]-HED. Recent studies have shown the utility of [11C]-HED in relevant clinical issues, such as in the elusive clinical syndrome of HFpEF. Conversely, tracers that target cardiac PNS innervation have been used less clinically, but novel tracers show potential utility for future work. The future application of [11C]-HED and newly designed 18F-labeled tracers for targeting the ANS hold promise for the evaluation and management of a wide range of cardiovascular diseases, including the prognostication of patients with HFpEF.

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Radiotracers for cardiac sympathetic innervation: Transport kinetics and binding affinities for the human norepinephrine transporter

Cited by 22 publications

References 18 publications

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

Consensus rank orderings of molecular fingerprints illustrate the ‘most genuine’ similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

Recent Advances and Clinical Applications of PET Cardiac Autonomic Nervous System Imaging

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