Radiosynthesis of an opiate receptor binding radiotracer: [11C]carfentanil

doi:10.1016/0020-708X(85)90089-4

The International Journal of Applied Radiation and Isotopes

Volume 36, Issue 4, April 1985, Pages 303-306

https://doi.org/10.1016/0020-708X(85)90089-4 Get rights and content

Abstract

Carfentanil, a potent opiate receptor agonist, was labeled with ¹¹C for in vito studies using positron emission tomography. This synthesis was completed in approximately 30 min using iodomethane as the ¹¹C precursor. The synthesis, purification, characterization, and determination of specific activity are presented and discussed.

References (5)

K.D. Stahl et al.
Eur. J. Pharmacol.
(1977)
J. Leysen et al.
Eur. J. Pharmacol.
(1977)

There are more references available in the full text version of this article.

Cited by (140)

Tactics for preclinical validation of receptor-binding radiotracers
2017, Nuclear Medicine and Biology
Citation Excerpt :
By contrast, an antagonist produces no effects, but can block those of agonists. In particular, potent agonists are used for opioid receptor PET [60,61,67], including [11C]-carfentanil, which is so active pharmacologically that the non-radioactive form is used to immobilize wild animals. The main effect is respiratory depression, and the carrier considered to be sub-pharmacological for a PET scan is less than 0.03 μg/kg [108].
Aspects of radiopharmaceutical development are illustrated through preclinical studies of [¹²⁵I]-(E)-1-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-4-(iodoallyl)piperazine ([¹²⁵I]-E-IA-BF-PE-PIPZE), a radioligand for sigma-1 (σ₁) receptors, coupled with examples from the recent literature. Findings are compared to those previously observed for [¹²⁵I]-(E)-1-(2-(2,3-dimethoxy-5-yl)ethyl)-4-(iodoallyl)piperazine ([¹²⁵I]-E-IA-DM-PE-PIPZE).
Syntheses of E-IA-BF-PE-PIPZE and [¹²⁵I]-E-IA-BF-PE-PIPZE were accomplished by standard methods. In vitro receptor binding studies and autoradiography were performed, and binding potential was predicted. Measurements of lipophilicity and protein binding were obtained. In vivo studies were conducted in mice to evaluate radioligand stability, as well as specific binding to σ₁ sites in brain, brain regions and peripheral organs in the presence and absence of potential blockers.
E-IA-BF-PE-PIPZE exhibited high affinity and selectivity for σ₁ receptors (K_i = 0.43 ± 0.03 nM, σ₂/σ₁ = 173). [¹²⁵I]-E-IA-BF-PE-PIPZE was prepared in good yield and purity, with high specific activity. Radioligand binding provided dissociation (k_off) and association (k_on) rate constants, along with a measured K_d of 0.24 ± 0.01 nM and B_max of 472 ± 13 fmol/mg protein. The radioligand proved suitable for quantitative autoradiography in vitro using brain sections. Moderate lipophilicity, Log D_7.4 2.69 ± 0.28, was determined, and protein binding was 71 ± 0.3%. In vivo, high initial whole brain uptake, >6% injected dose/g, cleared slowly over 24 h. Specific binding represented 75% to 93% of total binding from 15 min to 24 h. Findings were confirmed and extended by regional brain biodistribution. Radiometabolites were not observed in brain (1%).
Substitution of dihydrobenzofuranylethyl for dimethoxyphenethyl increased radioligand affinity for σ₁ receptors by 16-fold. While high specific binding to σ₁ receptors was observed for both radioligands in vivo, [¹²⁵I]-E-IA-BF-PE-PIPZE displayed much slower clearance kinetics than [¹²⁵I]-E-IA-DM-PE-PIPZE. Thus, minor structural modifications of σ₁ receptor radioligands lead to major differences in binding properties in vitro and in vivo.
Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: Implications for clinical use and policy
2014, Drug and Alcohol Dependence
Citation Excerpt :
During detoxification, BUP doses are most often tapered over one to several weeks, usually by halving the dose at each step from the maintenance level (Amass et al., 2004; Ling et al., 2009; Sigmon et al., 2013). The high-affinity, μOR-specific PET radioligand, [11C]-carfentanil (Dannals et al., 1985; Frost et al., 1985; Titeler et al., 1989) offers researchers a reliable and non-invasive means to map brain regional μOR availability. To adhere to the literature, we will refer to changes in receptor availability, which is an indirect measure.
Sublingual formulations of buprenorphine (BUP) and BUP/naloxone have well-established pharmacokinetic and pharmacodynamic profiles, and are safe and effective for treating opioid use disorder. Since approvals of these formulations, their clinical use has increased. Yet, questions have arisen as to how BUP binding to mu-opioid receptors (μORs), the neurobiological target for this medication, relate to its clinical application. BUP produces dose- and time-related alterations of μOR availability but some clinicians express concern about whether doses higher than those needed to prevent opioid withdrawal symptoms are warranted, and policymakers consider limiting reimbursement for certain BUP dosing regimens.
We review scientific data concerning BUP-induced changes in μOR availability and their relationship to clinical efficacy.
Withdrawal suppression appears to require ≤50% μOR availability, associated with BUP trough plasma concentrations ≥1 ng/mL; for most patients, this may require single daily BUP doses of 4 mg to defend against trough levels, or lower divided doses. Blockade of the reinforcing and subjective effects of typical doses of abused opioids require <20% μOR availability, associated with BUP trough plasma concentrations ≥3 ng/mL; for most individuals, this may require single daily BUP doses >16 mg, or lower divided doses. For individuals attempting to surmount this blockade with higher-than-usual doses of abused opioids, even larger BUP doses and <10% μOR availability would be required.
For these reasons, and given the complexities of studies on this issue and comorbid problems, we conclude that fixed, arbitrary limits on BUP doses in clinical care or limits on reimbursement for this care are unwarranted.
Evaluation of the agonist PET radioligand [11C]GR103545 to image kappa opioid receptor in humans: Kinetic model selection, test-retest reproducibility and receptor occupancy by the antagonist PF-04455242
2014, NeuroImage
Citation Excerpt :
As such, KOR is a target for development of newer antidepressants. There have been no prior reports of validated PET radiotracers for use in humans to image the KOR, although several tracers have been proposed and validated for MOR (Dannals et al., 1985), for MOR and KOR (Pert et al., 1984), and for DOR (Kinter and Lever, 1995). GR89696 ((±)-4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazine carboxylate) is a potent KOR agonist (Naylor et al., 1993).
Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human positron emission tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [¹¹C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test–retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (V_ND) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated.
For determination of a kinetic model and evaluation of test–retest reproducibility, 11 subjects were scanned twice with [¹¹C]GR103545. Seven subjects were scanned before and 75 min after oral administration of naltrexone (150 mg). For the KOR occupancy study, six subjects were scanned at baseline and 1.5 h and 8 h after an oral dose of PF-04455242 (15 mg, n = 1 and 30 mg, n = 5). Metabolite-corrected arterial input functions were measured and all scans were 150 min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (V_T). Relative test–retest variability (TRV), absolute test–retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test–retest reproducibility of regional V_T. Occupancy plots were computed for blocking studies to estimate occupancy and V_ND. The half maximal inhibitory concentration (IC₅₀) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [¹¹C]GR103545 in vivo K_D was also estimated.
Regional TACs were well described by the 2TC model and MA1. However, 2TC V_T was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test–retest variability was ~ 15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that V_T was reduced in all regions; thus no suitable reference region is available for the radiotracer. V_ND was estimated reliably from the occupancy plot of naltrexone blocking (V_ND = 3.4 ± 0.9 mL/cm³). The IC₅₀ of PF-04455242 was calculated as 55 ng/mL. [¹¹C]GR103545 in vivo K_D value was estimated as 0.069 nmol/L.
[¹¹C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy.
The Synthesis of Biphasic Metabolites of Carfentanil
2023, Molecules
Optimization of a Nucleophilic Two-Step Radiosynthesis of 6-O-(2-[18F]fluoroethyl)-6-O-desmethyl-diprenorphine ([18F]FE-DPN) for PET Imaging of Brain Opioid Receptors
2023, International Journal of Molecular Sciences
A Molecular Toolbox of Positron Emission Tomography Tracers for General Anesthesia Mechanism Research
2023, Journal of Medicinal Chemistry

View all citing articles on Scopus

View full text

Article preview

The International Journal of Applied Radiation and Isotopes

Abstract

References (5)

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Cited by (140)

Tactics for preclinical validation of receptor-binding radiotracers

Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: Implications for clinical use and policy

Evaluation of the agonist PET radioligand [<sup>11</sup>C]GR103545 to image kappa opioid receptor in humans: Kinetic model selection, test-retest reproducibility and receptor occupancy by the antagonist PF-04455242

The Synthesis of Biphasic Metabolites of Carfentanil

Optimization of a Nucleophilic Two-Step Radiosynthesis of 6-O-(2-[<sup>18</sup>F]fluoroethyl)-6-O-desmethyl-diprenorphine ([<sup>18</sup>F]FE-DPN) for PET Imaging of Brain Opioid Receptors

A Molecular Toolbox of Positron Emission Tomography Tracers for General Anesthesia Mechanism Research