New Norepinephrine-Depleting Agents. β-Hydroxyphenethylguanidine and Related Compounds

Green, A. L.; Fielden, R.; Bartlett, David; Cozens, Mary J.; Eden, R. J.; Hills, D. W.

doi:10.1021/jm00318a004

Cited by 12 publications

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“…To achieve this goal, radiolabeled phenethylguanidines were investigated because several phenethylguanidines are potent neuron blocking agents due to their prolonged retention inside norepinephrine storage vesicles. − The isolated rat heart studies with [ 18 F] 1 and [ 18 F] 2 presented above (Figure ) demonstrate that these compounds satisfy the targeted properties (a), (b), and (d). PET studies showing very long neuronal retention times for [ 18 F] 1 and [ 18 F] 2 in nonhuman primate myocardium are consistent with (b) rapid vesicular uptake and (d) very little diffusion of the tracers from storage vesicles.…”

Section: Results and Discussionmentioning

confidence: 86%

“…29–31 The isolated rat heart studies with [ 18 F] 1 and [ 18 F] 2 presented above (Figure 2) demonstrate that these compounds satisfy the targeted properties (a), (b) and (d). PET studies showing very long neuronal retention times for [ 18 F] 1 and [ 18 F] 2 in non-human primate myocardium are consistent with (b) rapid vesicular uptake and (d) very little diffusion of the tracers from storage vesicles.…”

Section: Resultsmentioning

confidence: 98%

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[¹⁸F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation

Jung

Jang

et al. 2017

ACS Chem. Neurosci.

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Fluorine-18 labeled phenethylguanidines are currently under development in our laboratory as radiotracers for quantifying regional cardiac sympathetic nerve density using PET imaging techniques. In this study, we report an efficient synthesis of 18F-hydroxyphenethylguanidines consisting of nucleophilic aromatic [18F]fluorination of a protected diaryliodonium salt precursor followed by a single deprotection step to afford the desired radiolabeled compound. This approach has been shown to reliably produce 4-[18F]fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG, [18F]1) and its structural isomer 3-[18F]fluoro-p-hydroxyphenethylguanidine ([18F]3F-PHPG, [18F]2) with good radiochemical yields. Preclinical evaluations of [18F]2 in non-human primates were performed to compare its imaging properties, metabolism, and myocardial kinetics with those obtained previously with [18F]1. The results of these studies have demonstrated that [18F]2 exhibits imaging properties comparable to those of [18F]1. Myocardial tracer kinetic analysis of each tracer provides quantitative metrics of cardiac sympathetic nerve density. Based on these findings, first-in-human PET studies with [18F]1 and [18F]2 are currently in progress to assess their ability to accurately measure regional cardiac sympathetic denervation in patients with heart disease, with the ultimate goal of selecting a lead compound for further clinical development.

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Section: Results and Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 98%

[¹⁸F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation

Jung

Jang

et al. 2017

ACS Chem. Neurosci.

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“…In particular, we chose to study phenethylguanidines because some of these compounds are known to be potent depletors of cardiac norepinephrine stores in vivo , due to their avid uptake and retention inside norepinephrine storage vesicles. 11 …”

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confidence: 99%

Synthesis and bioevaluation of [18F]4-fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG): A novel radiotracer for quantitative PET studies of cardiac sympathetic innervation

Jang

Jung

Sherman

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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A new cardiac sympathetic nerve imaging agent, [18F]4-fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG), was synthesized and evaluated. The radiosynthetic intermediate [18F]4-fluoro-m-tyramine ([18F]4F-MTA) was prepared and then sequentially reacted with cyanogen bromide and NH4Br/NH4OH to afford [18F]4F-MHPG. Initial bioevaluations of [18F]4F-MHPG (biodistribution studies in rats and kinetic studies in the isolated rat heart) were similar to results previously reported for the carbon-11 labeled analog [11C]4F-MHPG. The neuronal uptake rate of [18F]4F-MHPG into the isolated rat heart was 0.68 ml/min/g wet and its retention time in sympathetic neurons was very long (T1/2 > 13 h). A PET imaging study in a nonhuman primate with [18F]4F-MHPG provided high quality images of the heart, with heart-to-blood ratios at 80–90 min after injection of 5-to-1. These initial kinetic and imaging studies of [18F]4F-MHPG suggest that this radiotracer may allow for more accurate quantification of regional cardiac sympathetic nerve density than is currently possible with existing neuronal imaging agents.

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“…The preparation of 83-hydroxyphenethylguanidine sulphate and its optical isomers (Green, Fielden, Bartlett, Cozens, Eden & Hills, 1967), and of (-)-N-(l-phenylethyl)guanidine sulphate, N-[l-(2,4-xylyl)ethyl] guanidine sulphate and N-benzyl-N-methylguanidine sulphate (Fielden, Green & Willey, 1965) have been previously described. Other drugs were obtained commercially.…”

Section: Drugsmentioning

confidence: 99%

Optical Isomers of Β‐hydroxyphenethylguanidine: Effects on Heart Noradrenaline and on Sympathetic Blockade

Fielden¹,

Green

1968

British Journal of Pharmacology and Chemotherapy

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New Norepinephrine-Depleting Agents. β-Hydroxyphenethylguanidine and Related Compounds

Cited by 12 publications

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[¹⁸F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation

[¹⁸F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation

Synthesis and bioevaluation of [18F]4-fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG): A novel radiotracer for quantitative PET studies of cardiac sympathetic innervation

Optical Isomers of Β‐hydroxyphenethylguanidine: Effects on Heart Noradrenaline and on Sympathetic Blockade

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New Norepinephrine-Depleting Agents. β-Hydroxyphenethylguanidine and Related Compounds

Cited by 12 publications

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[18F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation

[18F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation

Synthesis and bioevaluation of [18F]4-fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG): A novel radiotracer for quantitative PET studies of cardiac sympathetic innervation

Optical Isomers of Β‐hydroxyphenethylguanidine: Effects on Heart Noradrenaline and on Sympathetic Blockade

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[¹⁸F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation

[¹⁸F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation