N-(3-[18F]Fluoropropyl)-N-nordiprenorphine: synthesis and characterization of a new agent for imaging opioid receptors with positron emission tomography

Chesis, Paul L.; Hwang, Dah‐Ren; Welch, Michael J.

doi:10.1021/jm00167a031

Cited by 25 publications

(22 citation statements)

References 2 publications

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“…Although this fluoroalkylation decreased the in vitro affinity of the analog, in vivo studies showed some retention of specific binding. Additional analogs have been described by Chesis et al . Their in vitro and in vivo results were quite similar to the earlier paper; however, there appears to have been no subsequent in vivo PET publications for these analogs.…”

Section: Radiotracers That Bind To Multiple Subtypessupporting

confidence: 74%

Positron emission tomography radioligands for the opioid system

Dannals

2013

Labelled Comp Radiopharmac

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Opiate receptors are found in the brain, the spinal cord, some peripheral sensory neurons, and the gastrointestinal tract. Naturally occurring and synthetic opiate ligands exert their influence on a wide variety of processes including analgesia, euphoria, dysphoria, sedation, respiratory depression, and miosis and are frequently topics for discussions on addiction and physical dependence. This review looks at the history of positron emission tomography radioligands for probing this receptor system.

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Section: Radiotracers That Bind To Multiple Subtypessupporting

confidence: 74%

Positron emission tomography radioligands for the opioid system

Dannals

2013

Labelled Comp Radiopharmac

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“…The use of the iodoallyl prosthetic group for incorporation of radioiodine is essential because direct iodination of the phenolic ring of morphinans such as DPN leads to a severe loss in opioid receptor binding potency (Casy and Parfitt, 1986). Similarly, modification at the N-position by iodoalkyl (Chesis et al, 1990) or iodoallyl moieties is not well-tolerated. By contrast, high affinity is maintained for morphinans substituted with bulky groups at the C6-position (Hazum et al, 1982;Kolb et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

Autoradiographic and SPECT imaging of cerebral opioid receptors with an iodine‐123 labeled analogue of diprenorphine

Lever¹,

Ilgìn²,

Musachio³

et al. 1998

Synapse

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The feasibility of imaging cerebral opioid receptors by single photon emission computed tomography (SPECT) has been established in baboon using a novel analog of diprenorphine (DPN) radiolabeled with iodine-123. The radioligand, [123I]-O-IA-DPN (C6-O-[123I]iodoallyl-DPN), was prepared in good yield (80%) with high radiochemical purity (>97%) and high specific radioactivity (>2,400 mCi/micromol). In ex vivo autoradiographic studies, with and without naltrexone blockade, [123I]-O-IA-DPN specifically labeled opioid receptors throughout the mouse brain. Nonmetabolized radioligand accounted for >90% of the signal observed in extracts of whole mouse brain. SPECT imaging trials showed that [123I]-O-IA-DPN selectively localized in regions of baboon brain known to have high densities of opioid receptors, such as striatum, thalamus, and temporal cortex. A much lower level of radioligand uptake and retention was noted for cerebellum, a region with few opioid binding sites. Pretreatment with naltrexone (6.5 pmol/kg) blocked [123I]-O-IA-DPN binding in all brain regions. Using naltrexone blockade to define the nonspecific component for a given region of interest, total to nonspecific binding ratios increased linearly (r > or = 0.98) over the SPECT study with maximal values for striatum (9.8), thalamus (7.1), and temporal cortex (6.9) reached at the last time point investigated (3.5 h). Specific binding for these regions, assessed as the difference between regional SPECT activity for the control and blocked states, proved irreversible over the observation period. By the end of the time course, specific [123I]-O-IA-DPN binding was >85% of total radioactivity in regions rich in opioid receptors and 62% of total radioactivity in cerebellum. The aggregate data are consistent with visualization of multiple opioid receptor types. Thus, [123I]-O-IA-DPN should prove useful for SPECT studies within the constraints imposed by a lack of innate selectivity for a single type of brain opioid receptor.

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“…Compartmental modeling and reference tissue methods generate quantitative parametric maps of [ 18 F]fluoroethyldiprenorphine binding in human brain [149], the tracer is in use for studies of nociceptive pathways [150], and single-bolus protocols are under development to allow measurements of endogenous opioid release in a single imaging session [151]. Properties for PET are superior to those of previously studied ligands having N-[ 18 F]fluoroalkyl groups in place of the cyclopropylmethyl [152,153].…”

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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N-(3-[18F]Fluoropropyl)-N-nordiprenorphine: synthesis and characterization of a new agent for imaging opioid receptors with positron emission tomography

Cited by 25 publications

References 2 publications

Positron emission tomography radioligands for the opioid system

Positron emission tomography radioligands for the opioid system

Autoradiographic and SPECT imaging of cerebral opioid receptors with an iodine‐123 labeled analogue of diprenorphine

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

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