Automated radiosyntheses of [6-O-methyl-11C]diprenorphine and [6-O-methyl-11C]buprenorphine from 3-O-trityl protected precursors

Luthra, Sajinder K.; Brady, F.; Turton, David R.; Brown, D J; Dowsett, Keith; Waters, S.L.; Jones, Anthony K.P.; Matthews, R. W.; Crowder, John

doi:10.1016/0969-8043(94)90217-8

Cited by 40 publications

(30 citation statements)

References 30 publications

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“…24 These demethylation conditions are unique to the orvinols, and offer convenient entry to the otherwise inaccessible C6-hydroxyl. They were serendipitously discovered for simpler members of the series by Kopcho and Schaeffer, 25 who suggested that the C6– O -methyl group is activated by formation of a six-membered ring complex between the C6– O , aluminum and an electron-rich atom ( O or N ) at C19, and then removed by S N 2 attack of an unknown nucleophile.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…24a Acid-labile t -butyldimethylsilyl or trityl ethers have been employed for protection of the phenol. 24 The more stable trityl moiety is preferred in recent fully automated radiosyntheses of DPN and other orvinols for clinical PET. 26 We reasoned that a tosyl protecting group would be advantageous for the present multi-step approach (vide infra) by providing stable intermediates compatible with deprotection under basic conditions.…”

Section: Resultsmentioning

confidence: 99%

“…Triol 1 , 6- O -desmethyl-diprenorphine, was prepared from DPN as previously reported and displayed appropriate 1 H NMR spectral data. 24a,c DOTA-NHS was purchased from Macrocyclics, Inc. (Plano, TX). DAMGO, NTI and U69,593 were from Sigma-RBI (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and opioid receptor binding of indium (III) and [111In]-labeled macrocyclic conjugates of diprenorphine: novel ligands designed for imaging studies of peripheral opioid receptors

et al. 2016

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Radiolabeled diprenorphine (DPN) and analogs are widely used ligands for non-invasive brain imaging of opioid receptors. To develop complementary radioligands optimized for studies of the peripheral opioid receptors, we prepared a pair of hydrophilic DPN derivatives, conjugated to the macrocyclic chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), for complexation with trivalent metals. The non-radioactive indium (III) complexes, tethered to the C6-oxygen position of the DPN scaffold by 6- to 9-atom spacers, displayed high affinities for binding to μ, δ and κ opioid receptors in vitro. Use of the 9-atom linker conferred picomolar affinities equipotent to those of the parent ligand DPN. The [111In]-labeled complexes were prepared in good yield (>70%), with high radiochemical purity (~99%) and high specific radioactivity (>4000 mCi/μmol). Their log D7.4 values were −2.21 to −1.66. In comparison, DPN is lipophilic, with a log D7.4 of +2.25. Further study in vivo is warranted to assess the suitability of these [111In]-labeled DPN-DOTA conjugates for imaging trials.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Synthesis and opioid receptor binding of indium (III) and [111In]-labeled macrocyclic conjugates of diprenorphine: novel ligands designed for imaging studies of peripheral opioid receptors

et al. 2016

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“…Tagging the C6-methoxy is advantageous, since a main route of metabolism for 4,5-epoxymorphinans is Ndecyclopropylmethylation [146]. Additional modifications, such as use of a stable trityl group for phenol protection, rendered the automated production methods for [ 11 C]diprenorphine and [ 11 C]buprenorphine that are used today [147].…”

Section: [ 11 C]diprenorphine [ 18 F]cyclofoxy and Other Ligands Formentioning

confidence: 99%

PET and SPECT Imaging of the Opioid System: Receptors, Radioligands and Avenues for Drug Discovery and Development

Lever¹

2007

CPD

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As we celebrate the bicentennial of the isolation of morphine by Sertürner, opioids continue to dominate major sectors of the analgesic market worldwide. The pharmaceutical industry stands to benefit greatly from molecular imaging in preclinical and early clinical trials of new or improved opioid drugs. At this juncture, it seems fitting to summarize the past twenty or so years of research on molecular imaging of the opioid system from the viewpoint of drug discovery and development. Opioid receptors were first imaged in human volunteers by positron emission tomography (PET) in 1984. Now, quantitative PET imaging of the major opioid receptor types (micro, delta , kappa) is possible in the brain and peripheral organs of healthy persons and patient populations. Radioligands are under development for single photon emission computed tomography (SPECT) of opioid receptors as well. These functional, nuclear imaging techniques can trace the fate of radiolabeled molecules directly, but non-invasively, and allow precise pharmacokinetic and pharmacodynamic measurements. Molecular imaging provides unique data that can aid in selecting the best drug candidates, determining optimal dosing regimens, clearing regulatory hurdles and lowering risks of failure. Using a historical perspective, this review touches on opioid receptors as drug targets, and focuses on the status and use of radiotracers for opioid receptor PET and SPECT. Selected studies are discussed to illustrate the power of molecular imaging for facilitating opioid drug discovery and development.

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Building on a 50‐year legacy of the MRC Cyclotron Unit: the Hammersmith radiochemistry pioneering journey

Brady¹,

Clark²,

Luthra³

2007

Labelled Comp Radiopharmac

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The Medical Research Council Cyclotron Unit (MRC CU) situated at Hammersmith Hospital, London, is widely recognised for its pioneering developments in radiochemistry. The MRC CU became one of the largest and most comprehensive PET centres in the world. More recently, under the umbrella of a public/private partnership between the MRC and Amersham Health (now part of GE Healthcare) this centre has continued to advance PET research.This article reviews the 50-year history of radiochemistry development and application for medical research at Hammersmith.

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Automated radiosyntheses of [6-O-methyl-11C]diprenorphine and [6-O-methyl-11C]buprenorphine from 3-O-trityl protected precursors

Cited by 40 publications

References 30 publications

Synthesis and opioid receptor binding of indium (III) and [111In]-labeled macrocyclic conjugates of diprenorphine: novel ligands designed for imaging studies of peripheral opioid receptors

Synthesis and opioid receptor binding of indium (III) and [111In]-labeled macrocyclic conjugates of diprenorphine: novel ligands designed for imaging studies of peripheral opioid receptors

PET and SPECT Imaging of the Opioid System: Receptors, Radioligands and Avenues for Drug Discovery and Development

Building on a 50‐year legacy of the MRC Cyclotron Unit: the Hammersmith radiochemistry pioneering journey

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