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

Abstract

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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“…S3E). Direct measurement of NE uptake by PET imaging of 11 C-metahydroxyephedrine, a NE analog (8,38), revealed that rimonabant increased tracer uptake in the BAT of both free-fed and fasted animals ( Fig. S3F).…”

Molecular Imaging of Cardiac Sympathetic Innervation by 11C-mHED and PET: From Man to Mouse?

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