Metabolic fate of the heart agent [18F]6-fluorometaraminol

doi:10.1016/0883-2897(89)90147-5

International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology

Volume 16, Issue 7, 1989, Pages 735-739

International Journa...

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Abstract

Studies were performed to determine whether [¹⁸F]6-fluorometaraminol (¹⁸F-FMR), a new neuronal heart radiopharmaceutical, is metabolized in vivo and if the metabolites are taken up in heart. Rat, dog, baboon and guinea pig were injected with ¹⁸F-FMR and tissue samples were analyzed for metabolites by HPLC. Liver contained the most metabolites of the tissues studied with 25–90% of the radioactivity present as metabolites at 1 h in all the species studied. While metabolites of ¹⁸F-FMR are found in blood, no significant accumulation of these metabolites is found in heart (⩽0.3%) 1 h after i.v. administration in any species except rat. These studies suggest that ¹⁸F-FMR is a suitable agent for quantitative imaging of the heart by positron emission tomography.

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Cited by (13)

18F-Labeled PET-Tracers for Cardiological Imaging
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Molecular imaging of the myocardium being the functionally most relevant tissue compartment of the mammalian heart has been proven valuable for clinical diagnostics, especially for the evaluation of cardiac physiology and pathophysiology. Molecular and functional imaging of myocytes, vessels, and nerves in the human heart is already established using different 18F-containing compounds and highly promising for future diagnostic use in patients. 2-Deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) and ¹⁸F-labeled fatty acids are suitable tracers for the imaging of the metabolism of the myocardium and used for the investigation of metabolic abnormalities that underlie cardiac dysfunction. Myocardial metabolism can be extensively and quantitatively investigated with positron emission tomography (PET). To maintain heart rate and cardiac contraction even in cardiac stress situations, the healthy human heart has to constantly extract arterial oxygen with high efficiency. However, myocardial oxygen extraction reaches its maximum already in the resting state. Thus, the only backdoor to further enhance myocardial oxygen supply in stress situations is the dilation of the coronary arteries to increase the myocardial blood volume. Because of changes in substrate utilization as a result of oxygen availability, it is useful to combine metabolic imaging and the assessment of myocardial blood flow in one PET session. Atherosclerosis is a progressive vascular fibroproliferative-inflammatory disease. It is triggered, maintained, and driven by risk factors such as hypercholesterolemia, hyperlipidemia, and hypertonus. The characteristic clinical manifestation of atherosclerosis is the atherosclerotic lesion, developing in the vessel wall (atherosclerotic plaque). One approach of imaging vulnerable atherosclerotic plaques is based on the assessment of the degree of inflammation within the unstable lesions. Therefore, the measurement of macrophage-based metabolic activity by [¹⁸F]FDG PET is of potential use.
18F-Labeled PET-Tracers for Cardiological Imaging
2008, Fluorine and Health
Molecular imaging of the myocardium being the functionally most relevant tissue compartment of the mammalian heart has been proven valuable for clinical diagnostics, especially for the evaluation of cardiac physiology and pathophysiology. Molecular and functional imaging of myocytes, vessels, and nerves in the human heart is already established using different 18F-containing compounds and highly promising for future diagnostic use in patients. 2-Deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) and ¹⁸F-labeled fatty acids are suitable tracers for the imaging of the metabolism of the myocardium and used for the investigation of metabolic abnormalities that underlie cardiac dysfunction. Myocardial metabolism can be extensively and quantitatively investigated with positron emission tomography (PET). To maintain heart rate and cardiac contraction even in cardiac stress situations, the healthy human heart has to constantly extract arterial oxygen with high efficiency. However, myocardial oxygen extraction reaches its maximum already in the resting state. Thus, the only backdoor to further enhance myocardial oxygen supply in stress situations is the dilation of the coronary arteries to increase the myocardial blood volume. Because of changes in substrate utilization as a result of oxygen availability, it is useful to combine metabolic imaging and the assessment of myocardial blood flow in one PET session. Atherosclerosis is a progressive vascular fibroproliferative-inflammatory disease. It is triggered, maintained, and driven by risk factors such as hypercholesterolemia, hyperlipidemia, and hypertonus. The characteristic clinical manifestation of atherosclerosis is the atherosclerotic lesion, developing in the vessel wall (atherosclerotic plaque). One approach of imaging vulnerable atherosclerotic plaques is based on the assessment of the degree of inflammation within the unstable lesions. Therefore, the measurement of macrophage-based metabolic activity by [¹⁸F]FDG PET is of potential use.
A novel electrophilic synthesis and evaluation of medium specific radioactivity (1R,2S)-4-[18F]fluorometaraminol, a tracer for the assessment of cardiac sympathetic nerve integrity with PET
2004, Nuclear Medicine and Biology
(1R,2S)-4-[¹⁸F]fluorometaraminol (4-[¹⁸F]FMR), a tracer for cardiac sympathetic innervation, was synthesized by electrophilic aromatic substitution. A trimethylstannyl precursor, protected with tert-butoxycarbonyl protecting groups, was radiofluorinated with high specific radioactivity [¹⁸F]F₂. Specific radioactivity of 4-[¹⁸F]FMR, in average 11.8 ±3.3 GBq/μmol, was improved 40-800-fold in comparison to the previous electrophilic fluorinations. The biodistribution of 4-[¹⁸F]FMR in rat was in accordance with the known distribution of sympathetic innervation. 4-[¹⁸F]FMR showed no metabolic degradation in left ventricle of rat heart, where the uptake was high, rapid and specific.
Assessment of cardiac sympathetic nerve integrity with positron emission tomography
2001, Nuclear Medicine and Biology
The autonomic nervous system plays a critical role in the regulation of cardiac function. Abnormalities of cardiac innervation have been implicated in the pathophysiology of many heart diseases, including sudden cardiac death and congestive heart failure. In an effort to provide clinicians with the ability to regionally map cardiac innervation, several radiotracers for imaging cardiac sympathetic neurons have been developed. This paper reviews the development of neuronal imaging agents and discusses their emerging role in the noninvasive assessment of cardiac sympathetic innervation.
High specific radioactivity (1R,2S)-4-[18F]fluorometaraminol: A PET radiotracer for mapping sympathetic nerves of the heart
2000, Nuclear Medicine and Biology
The radiolabeled catecholamine analogue (1R,2S)-6-[¹⁸F]fluorometaraminol (6-[¹⁸F]FMR) is a substrate for the neuronal norepinephrine transporter. It has been used as a positron emission tomography (PET) ligand to map sympathetic nerves in dog heart. 6-[¹⁸F]FMR could be only synthesized with low specific radioactivity, which precluded its use in human subjects. We have recently prepared (1R,2S)-4-[¹⁸F]fluorometaraminol (4-[¹⁸F]FMR), a new fluoro-analogue of metaraminol, with high specific radioactivity (56–106 GBq/μmol). In the present study, we demonstrate in rats that 4-[¹⁸F]FMR possesses similar affinity toward myocardial norepinephrine transport mechanisms as 6-[¹⁸F]FMR. When compared with control animals, an 80% and 76% reduction in myocardial uptake was observed in animals pretreated with desipramine (an inhibitor of the neuronal norepinephrine transporter) and with reserpine (a blocker of the vesicular storage of monoamines), respectively. The entire radioactivity in rat myocardium represented unmetabolized parent tracer as determined by high performance liquid chromatography analysis of tissue extracts. In dogs, myocardial kinetics of 4-[¹⁸F]FMR were assessed using PET. A rapid and high uptake was observed, followed by prolonged cardiac retention. A heart-to-lung ratio of 15 was reached 10 min after injection of the radiotracer. Pretreatment with desipramine reduced the heart half-life of 4-[¹⁸F]FMR by 90% compared with control. Moreover, an infusion of tyramine caused a rapid decline of radioactivity in the heart. This demonstrates that 4-[¹⁸F]FMR specifically visualizes sympathetic neurons in dog heart. High specific radioactivity 4-[¹⁸F]FMR is a promising alternative to 6-[¹⁸F]FMR for myocardial neuronal mapping with PET in humans.
New horizons in cardiac innervation imaging: Introduction of novel 18F-labeled PET tracers
2017, European Journal of Nuclear Medicine and Molecular Imaging

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International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology

Abstract

References (14)

A rapid technique for the separation of thymocytes from suspension by centrifugation through silicon oil

Anal. Biochem.

Distribution of metaraminol and its relation to norepinephrine

Eur. J. Pharmacol.

Tissue levels of metaraminol and its metabolite, α-methylnorepinephrine, in control and 6-hydroxydopamine-pretreated guinea pigs

Life Sci.

Formation of α-methylnorepinephrine as a metabolite of metaraminol in guinea pigs

Biochem. Pharmacol.

Lack of metaraminol biotransformation by rabbit tissues in vitro

Biochem. Pharmacol.

Effect of route of administration and distribution on drug action

J. Pharmacokinetic Biopharm.

Uptake, storage and release of ³H-α-methyl-norepinephrine

J. Pharmacol. Exp. Ther.

Cited by (13)

18F-Labeled PET-Tracers for Cardiological Imaging

<sup>18</sup>F-Labeled PET-Tracers for Cardiological Imaging

A novel electrophilic synthesis and evaluation of medium specific radioactivity (1R,2S)-4-[<sup>18</sup>F]fluorometaraminol, a tracer for the assessment of cardiac sympathetic nerve integrity with PET

Assessment of cardiac sympathetic nerve integrity with positron emission tomography

High specific radioactivity (1R,2S)-4-[<sup>18</sup>F]fluorometaraminol: A PET radiotracer for mapping sympathetic nerves of the heart

New horizons in cardiac innervation imaging: Introduction of novel <sup>18</sup>F-labeled PET tracers

Metabolic fate of the heart agent [18F]6-fluorometaraminol

Abstract

Anal. Biochem.

Eur. J. Pharmacol.

Life Sci.

Biochem. Pharmacol.

Biochem. Pharmacol.

Effect of route of administration and distribution on drug action

J. Pharmacokinetic Biopharm.

Uptake, storage and release of 3H-α-methyl-norepinephrine

J. Pharmacol. Exp. Ther.

Metabolic fate of the heart agent [¹⁸F]6-fluorometaraminol

Uptake, storage and release of ³H-α-methyl-norepinephrine