Biodistribution and Metabolism of [N-methyl-11C]-m-hydroxyephedrine in the Rat

Law, Marilyn P.

doi:10.1016/s0969-8051(97)00007-3

Nuclear Medicine and Biology

1997

DOI: 10.1016/s0969-8051(97)00007-3

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Biodistribution and Metabolism of [N-methyl-11C]-m-hydroxyephedrine in the Rat

Marilyn P. Law¹

Abstract: Biodistribution and metabolism of [N-methyl-11C]m-hydroxyephedrine ([11C]mHED), an analogue of noradrenaline, were assessed in rats. Pretreatment with desipramine, an uptake blocker, reduced uptake of radioactivity in myocardium but not in lung, liver, kidney, and muscle. Brain uptake was negligible. HPLC showed six radioactive metabolites in plasma and liver but none in myocardium. Co-injection of unlabelled mHED or metaraminol with [11C]mHED demonstrated no difference between the in vivo binding potentials f… Show more

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Cited by 11 publications

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“…Moreover, HED is resistant to the NE-metabolizing enzymes monoamine oxidase (MAO) and catechol-Omethyltransferase (9). Characterization studies of HED have demonstrated dependence of retention on the functionality and availability of NET (12,13), confirming specificity in myocardium, spleen, and adrenal glands (9,11,14). Pharmacokinetic studies performed in animal models and isolated organ systems (2,9,11,15) have implied a correlation between NE concentration and clearance rate of HED (2,15).…”

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confidence: 89%

“…Characterization studies of HED have demonstrated dependence of retention on the functionality and availability of NET (12,13), confirming specificity in myocardium, spleen, and adrenal glands (9,11,14). Pharmacokinetic studies performed in animal models and isolated organ systems (2,9,11,15) have implied a correlation between NE concentration and clearance rate of HED (2,15). Metabolite analyses in rats, guinea pigs, dogs, and humans revealed that metabolites detected in plasma and liver are not present in cardiac tissue, facilitating qualitative image analysis and clinical interpretation (9,11,16).…”

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confidence: 89%

“…A growing body of evidence suggests that SNS dysfunction may be concomitantly involved in several cardiac pathologies (5,6), obesity (7), and diabetes mellitus (8). 11 C-meta-Hydroxyephedrine (HED) is routinely applied in cardiac PET to assess sympathetic innervation (9,10). As an analog of NE, the tracer is actively recaptured into the neuron via NET, providing a quantitative indication of presynaptic sympathetic nervous integrity and function (2,9,11).…”

mentioning

confidence: 99%

“…11 C-meta-Hydroxyephedrine (HED) is routinely applied in cardiac PET to assess sympathetic innervation (9,10). As an analog of NE, the tracer is actively recaptured into the neuron via NET, providing a quantitative indication of presynaptic sympathetic nervous integrity and function (2,9,11). Moreover, HED is resistant to the NE-metabolizing enzymes monoamine oxidase (MAO) and catechol-Omethyltransferase (9).…”

mentioning

confidence: 99%

“…Pharmacokinetic studies performed in animal models and isolated organ systems (2,9,11,15) have implied a correlation between NE concentration and clearance rate of HED (2,15). Metabolite analyses in rats, guinea pigs, dogs, and humans revealed that metabolites detected in plasma and liver are not present in cardiac tissue, facilitating qualitative image analysis and clinical interpretation (9,11,16).…”

mentioning

confidence: 99%

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Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

Thackeray¹,

Beanlands²,

DaSilva³

2007

Journal of Nuclear Medicine

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11 C-meta-Hydroxyephedrine (HED) is used in cardiac PET as an index of norepinephrine (NE) reuptake transporter (NET) density and synaptic NE levels. Whereas cardiac uptake is well documented, tracer retention in other tissues with rich noradrenergic innervation is unclear. Dysfunctional sympathetic nervous system (SNS) function in extracardiac metabolic storage tissues (i.e., adipose tissue and skeletal muscle) and endocrine organs contributes to several disorders. The aim of this study was to determine the potential of HED as an index of NE function in brown adipose tissue, lung, pancreas, skeletal muscle, and kidney by identifying NET-specific retention and determining the presence of radiolabeled metabolites. Methods: Male Sprague-Dawley rats were administered HED and sacrificed at 30 min after tracer injection. Tissues were rapidly excised and counted for radioactivity, and relative tracer retention was quantified. Pretreatment with NET inhibitors established specific HED accumulation. The effect of elevated NE was tested by subcutaneous minipump NE infusion or inhibition of monoamine oxidase. Column-switch high-performance liquid chromatography (HPLC) was used to analyze the presence of radiolabeled metabolites in heart, brown adipose tissue, pancreas, and plasma. Results: NET-specific retention was observed in heart, brown adipose tissue, lung, and pancreas but not in liver, skeletal muscle, or kidney. A dosedependent response of HED accumulation to treatments elevating NE levels was established in tissues exhibiting specific uptake. At 30 min after tracer administration, HPLC analysis revealed 93%-95% of total radioactivity signal derived from unchanged HED in heart, pancreas, and brown adipose tissue compared with 61% 6 8% unchanged HED in plasma. Conclusion: In addition to the heart, lung, pancreas, and brown adipose tissue exhibit specific and NE-responsive uptake of HED, supporting the potential for novel PET studies of SNS integrity in these tissues.Key Words: sympathetic nervous system function; norepinephrine transporter uptake-1; competition with norepinephrine; HPLC column-switch system The sympathetic nervous system (SNS) is a primary extrinsic control mechanism mediating cardiac function, metabolic processes, and adaptation to stress. In normal conditions, the neurotransmitter norepinephrine (NE) is released from the presynaptic bouton into the synapse, where it binds to and stimulates adrenoceptors on pre-and postsynaptic cells. Excess NE is recycled into the presynaptic neuron by active transport via the uptake-1 NE reuptake transporter (NET) (1,2).In myocardium, the SNS modulates heart rate, cardiac output, and stroke volume (2). In metabolic storage tissues, SNS activation stimulates 2 key processes: lipolysis-the breakdown of lipids primarily in white adipocytes-and thermogenesis-the uncoupling of mitochondrial energetics promoting heat release over energy storage, primarily in brown adipocytes and skeletal muscle (3). The SNS also partially controls pancreatic secretion of insulin and gl...

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mentioning

confidence: 89%

mentioning

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

Thackeray¹,

Beanlands²,

DaSilva³

2007

Journal of Nuclear Medicine

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Evaluating presynaptic and postsynaptic innervation in heart failure

Chen¹,

Caldwell

2009

Curr Cardiol Rep

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Congestive heart failure increasingly contributes to the overall morbidity and mortality associated with cardiovascular disease. Although significant advances in therapies allow patients to feel better and have improved functional status and survival, not all patients respond equally to these therapies. Moreover, for any given level of left ventricular systolic dysfunction, it is difficult to predict who will have progressive heart failure leading to death or transplantation or who will die suddenly. It has long been recognized that the sympathetic nervous system plays a major role in the morbidity and mortality associated with congestive heart failure from systolic left ventricular dysfunction. Although some of the sympathetic effect occurs at the systemic level, malfunction at the ventricular myocyte-sympathetic nerve terminal interface is likely a major contributor to sudden death and progressive heart failure. Imaging the cardiac sympathetic nervous system can be used to evaluate this myoneural interface and to predict outcome.

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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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Biodistribution and Metabolism of [N-methyl-11C]-m-hydroxyephedrine in the Rat

Cited by 11 publications

References 0 publications

Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

Evaluating presynaptic and postsynaptic innervation in heart failure

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

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