High yield synthesis of high specific activity R-(−)-[11C]epinephrine for routine PET studies in humans

doi:10.1016/0969-8051(93)90094-B

Nuclear Medicine and Biology

Volume 20, Issue 8, November 1993, Pages 939-944

https://doi.org/10.1016/0969-8051(93)90094-B Get rights and content

Abstract

R-(−)-[¹¹C]Epinephrine ([¹¹C]EPI) has been synthesized from R-(−)-norepinephrine by direct methylation with [¹¹C]methyl iodide or [¹¹C]methyl triflate. The total synthesis time including HPLC purification was 35–40 min. The radiochemical yields (EOB) were 5–10% for [¹¹C]methyl iodide and 15–25% for [¹¹C]methyl triflate. Radiochemical purity was >98%; optical purity determined by radio-chiral HPLC was >97%. The [¹¹C]methyl triflate technique produces R-(−)-[¹¹C]epinephrine in quantities (80–170 mCi) sufficient for multiple positron emission tomography studies in humans. The two synthetic methods are generally applicable to the production of other N-[¹¹C]methyl phenolamines and N-[¹¹C]methyl catecholamines.

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Furthermore, the elution order of the enantiomers was altered by this mobile phase, probably due to the changing chiral stationary phase conformation. In a challenging study by Chakraborty [69] CCC was utilized to purify the racemic precursor mixture to obtain pure individual precursors (enantiomerically). This study enabled the purification of the enantiomers (R,R)-[11C]O-methyl reboxetine and (S,S)-[11C]O-methyl reboxetine which could be applied as a precursor in the preparation of a PET-RL, separately.
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(R,S)-Isoproterenol inhibits the formation of toxic granular tau oligomers associated with neuronal loss and development of cognitive disorders, and is an attractive drug candidate for Alzheimer’s disease. To elucidate its behavior in the brain by positron emission tomography, we synthesize (R,S)-[¹¹C]isoproterenol by reductive alkylation of (R,S)-norepinephrine with [2-¹¹C]acetone, which was in turn synthesized in situ under improved conditions afforded a decay-corrected radiochemical yield of 54%. The reductive alkylation using NaBH(OAc)₃ as reducing agent in the presence of benzoic acid in DMSO/DMF (60:40 v/v) at 100 °C for 10 min gave (R,S)-[¹¹C]isoproterenol in an 87% radio-high performance liquid chromatography (HPLC) analytical yield. HPLC separation using a strong cation exchange column, followed by pharmaceutical formulation in the presence of d/l-tartaric acid, afforded (R,S)-[¹¹C]isoproterenol with a total radioactivity of 2.0 ± 0.2 GBq, a decay-corrected radiochemical yield of 19 ± 2%, chemical and radiochemical purities of 71% and >99%, respectively, and a molar activity of 100 ± 13 GBq/μmol (n = 3). The overall synthesis time from the end of the bombardment to pharmaceutical formulation was 48 min. A preliminary preclinical PET study in a rat demonstrated the potential of the radioligand for the evaluation of the penetration of (R,S)-isoproterenol in human brain.
Exploring Metabolism In Vivo Using Endogenous 11C Metabolic Tracers
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The syntheses of endogenous steroids have been reported, including [17α-11C] methyltestosterone.76 Several neurotransmitters and their precursors have been studied, including 11C l-tyrosine,41 l-DOPA,77 l-tryptophan,31 5-hydroxy-l-tryptophan,31 11C epinephrine,78 and 11C norepinephrine.79 11C epinephrine has been used to study cardiac sympathetic nerve function in the context of heart transplantation because the latter is associated with decreased sympathetic nerve integrity.80
Cancer and other diseases are increasingly understood in terms of their metabolic disturbances. This thinking has revolutionized the field of ex vivo metabolomics and motivated new approaches to detect metabolites in living systems, including proton magnetic resonance spectroscopy (¹H-MRS), hyperpolarized ¹³C MRS, and PET. For PET, imaging abnormal metabolism in vivo is hardly new. Positron-labeled small-molecule metabolites have been used for decades in humans, including ¹⁸F-FDG, which is used frequently to detect upregulated glycolysis in tumors. Many current ¹⁸F metabolic tracers including ¹⁸F-FDG have evolved from their ¹¹C counterparts, chemically identical to endogenous substrates and thus approximating intrinsic biochemical pathways. This mimicry has stimulated the development of new radiochemical methods to incorporate ¹¹C and inspired the synthesis of a large number of ¹¹C endogenous radiotracers. This is in spite of the 20-minute half-life of ¹¹C, which generally limits its use in patients to centers with an on-site cyclotron. Innovation in ¹¹C chemistry has persisted in the face of this limitation, because (1) the radiochemists involved are inspired, (2) the methods of ¹¹C incorporation are diverse, and (3) ¹¹C compounds often show more predictable in vivo behavior, thus representing an important first step in the validation of new tracer concepts. In this mini-review we will discuss some of the general motivations behind PET tracers, rationales for the use of ¹¹C, and some of the special challenges encountered in the synthesis of ¹¹C endogenous compounds. Most importantly, we will try to highlight the exceptional creativity used in early ¹¹C tracer syntheses, which used enzyme-catalyzed and other “green” methods before these concepts were commonplace.
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Citation Excerpt :
Assessment of the kinetic profiles of these new compounds not only provides valuable structure–activity relation data but also allows comparisons with the existing radiotracers and biogenic amines. [11C]-(−)-meta-Hydroxyephedrine (HED) and [11C]-(−)-epinephrine (EPI) were prepared using previously published methods [6,7]. The five different [11C]-labeled phenethylguanidines studied were synthesized using methods previously reported [5].
Most radiotracers for imaging of cardiac sympathetic innervation are substrates of the norepinephrine transporter (NET). The goal of this study was to characterize the NET transport kinetics and binding affinities of several sympathetic nerve radiotracers, including [¹¹C]-(−)-meta-hydroxyephedrine, [¹¹C]-(−)-epinephrine, and a series of [¹¹C]-labeled phenethylguanidines under development in our laboratory. For comparison, the NET transport kinetics and binding affinities of some [³H]-labeled biogenic amines were also determined.
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K_m, V_max and K_I values were determined for each NET substrate with a high degree of reproducibility. Interestingly, C6-hNET transport rates for ‘tracer concentrations’ of substrate, given by the ratio V_max/K_m, were found to be highly correlated with neuronal transport rates measured previously in isolated rat hearts (r² = 0.96). This suggests that the transport constants K_m and V_max measured using the C6-hNET cells accurately reflect in vivo transport kinetics.
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Synthesis and bioevaluation of [18F]4-fluoro-m- hydroxyphenethylguanidine ([18F]4F-MHPG): A novel radiotracer for quantitative PET studies of cardiac sympathetic innervation
2013, Bioorganic and Medicinal Chemistry Letters
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 (T_1/2 >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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^☆: Parts of this study were first reported in abstract form: Chakraborty P. K., Gildersleeve D. L., Toorongian S. A., Kilbourn M. R., Schwaiger M. and Wieland D. M. (1993) Synthesis of [¹¹C]epinephrine and other biogenic amines by direct methylation of normethyl precursors. 9th International Symposium on Radiopharmaceutical Chemistry, 5–10 April 1992, Paris, France. J. Labeled Cmpd. Radiopharm.32, 172.

^†: Present address: Nuclear Medicine Department, SUNY at Buffalo, Buffalo, NY 14214, U.S.A.

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Nuclear Medicine and Biology

Abstract

References (17)

High-performance liquid chromatographic determination of d-/l-epinephrine enantiomer ratio in lidocaine-epinephrine local anesthetics

J. Chromatogr.

A simple synthesis of [¹¹C]methyl triflate

Appl. Radiat. Isot.

Synthesis of methyl iodide-¹¹C and formaldehyde-¹¹C

Int. J. Appl. Radiat. Isot.

Routine synthesis of N-[¹¹C-methyl]scopolamine by phosphite mediated reductive methylation with [¹¹C]formaldehyde

Appl. Radiat. Isot.

Synthesis of high specific activity 6-[¹⁸F]fluorodopamine for positron emission tomography studies of sympathetic nervous tissue

J. Med. Chem.

Synthesis of high specific activity (+)- and (−)-6-[¹⁸F]fluoronorepinephrine via the nucleophilic aromatic substitution reaction

J. Med. Chem.

Positron emission imaging of cardiac sympathetic innervation and function

Circulation

Positron emission imaging of cardiac sympathetic innervation and function using ¹⁸F-6-fluorodopamine: effects of chemical sympathectomy by 6-hydroxydopamine

J. Hypertension

Cited by (50)

Congestive Heart Failure

Application of chiral chromatography in radiopharmaceutical fields: A review

Synthesis of (R,S)-isoproterenol, an inhibitor of tau aggregation, as an <sup>11</sup>C-labeled PET tracer via reductive alkylation of (R,S)-norepinephrine with [2-<sup>11</sup>C]acetone

Exploring Metabolism In Vivo Using Endogenous <sup>11</sup>C Metabolic Tracers

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

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

High yield synthesis of high specific activity R-(−)-[11C]epinephrine for routine PET studies in humans☆

Abstract

J. Chromatogr.

Appl. Radiat. Isot.

Int. J. Appl. Radiat. Isot.

Appl. Radiat. Isot.

Synthesis of high specific activity 6-[18F]fluorodopamine for positron emission tomography studies of sympathetic nervous tissue

J. Med. Chem.

Synthesis of high specific activity (+)- and (−)-6-[18F]fluoronorepinephrine via the nucleophilic aromatic substitution reaction

J. Med. Chem.

Positron emission imaging of cardiac sympathetic innervation and function

Circulation

Positron emission imaging of cardiac sympathetic innervation and function using 18F-6-fluorodopamine: effects of chemical sympathectomy by 6-hydroxydopamine

J. Hypertension

High yield synthesis of high specific activity R-(−)-[¹¹C]epinephrine for routine PET studies in humans☆

Synthesis of high specific activity 6-[¹⁸F]fluorodopamine for positron emission tomography studies of sympathetic nervous tissue

Synthesis of high specific activity (+)- and (−)-6-[¹⁸F]fluoronorepinephrine via the nucleophilic aromatic substitution reaction

Positron emission imaging of cardiac sympathetic innervation and function using ¹⁸F-6-fluorodopamine: effects of chemical sympathectomy by 6-hydroxydopamine