US-12617816-B2 - Composition and method for in vivo assay of opioid receptors

Abstract

Compositions and methods are provided to determine occupancy level of opioid receptors in a subject. The disclosed methods may be performed non-invasively in the inner ear of the subject, and may be performed at a point-of-care location to provide guidance to a practitioner on tapering on pharmacotherapy or on a patient's risk of relapse for substance abuse.

Inventors

• Jonathan T. Elliott

Assignees

• THE TRUSTEES OF DARTMOUTH COLLEGE

Dates

Publication Date

20260505

Application Date

20201111

Claims (20)

1. 1 . A compound of formula (I) or a salt thereof:
2. 2 . A composition comprising the compound of claim 1 and a carrier.
3. 3 . A method for determining occupancy level of an opioid receptor in a subject, comprising: (a) contacting at least one probe with the subject, wherein the probe binds specifically to the opioid receptor (OR); (b) measuring intensity of fluorescent signal emitted by the probe from inner ear of the subject; and (c) determining the occupancy level of the opioid receptor in the subject based on the fluorescence intensity, wherein the probe comprises a compound having the formula (I) or a salt thereof:
4. 4 . The method of claim 3 , wherein step (b) is performed non-invasively.
5. 5 . The method of claim 3 , wherein fluorescence intensity in spiral ganglion is measured in step (b).
6. 6 . The method of claim 3 , wherein the fluorescence intensity is measured by using an oto-spectroscope.
7. 7 . The method of claim 3 , wherein the opioid receptor is mu opioid receptor (MOR).
8. 8 . The method of claim 3 , wherein the occupancy level of the opioid receptor in the subject is calculated quantitatively.
9. 9 . The method of claim 3 , further comprising administering an effective amount of an opioid antagonist or a partial opioid agonist to the subject based on the occupancy level of the opioid receptor in the subject.
10. 10 . The method of claim 9 , wherein the amount of the opioid antagonist or the partial opioid agonist administered is determined based on the occupancy level of the opioid receptor in the subject.
11. 11 . The method of claim 3 , wherein the probe is administered into the body of the subject in step (a).
12. 12 . The method of claim 3 , wherein the probe is administered by a means selected from the group consisting of nasal spray, intravenous (IV) injection, oral administration and skin patch.
13. 13 . The method of claim 3 , wherein the subject has been treated with a pain medication prescribed by a physician prior to step (a).
14. 14 . The method of claim 3 , wherein the method is used for preventing/treating opioid use disorder (OUD) or for monitoring response of a subject to treatment using an opioid antagonist.
15. 15 . The method of claim 3 , wherein the method is used for determining the dose of pharmacotherapy in the treatment of substance use disorder.
16. 16 . The method of claim 15 , wherein the substance use disorder is opioid use disorder.
17. 17 . The method of claim 15 , wherein the method is used to taper down the dosage of pharmacotherapy.
18. 18 . The method of claim 15 , wherein the subject is a pregnant woman with a substance use disorder and the method is used to reduce the risk of relapse in the subject.
19. 19 . The method of claim 3 , wherein excitation wavelength used in step (b) ranges between 635 nm and 760 nm.
20. 20 . The method of claim 3 , further comprising a step of measuring rate of internalization of the probe.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application is a 35 U.S.C. § 371 filing of International Application No. PCT/US2020/060035 filed Nov. 11, 2020, which claims benefit of priority to U.S. Provisional Patent Application No. 62/933,644 filed on Nov. 11, 2019, which is incorporated herein by reference in its entirety. GOVERNMENT RIGHTS This invention was made with government support under grant number R21 EB024771 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD The present disclosure relates to compositions and methods for in vivo determination of mu-opioid receptor expression and activity for the prevention, diagnosis and treatment of opioid use disorder (OUD). BACKGROUND Opioid is currently an important point for managing clinically significant pain. Opioid receptors (OR) are abundant in the central nervous system and the peripheral nervous system. Activation of opioid receptors is useful clinically to produce analgesia; however, agonists such as morphine, fentanyl and its derivatives, and heroin, produce chemical dependence, a condition termed opioid use disorder (OUD). Deaths caused by OUD and opioid overdose now exceed those caused by motor vehicle accidents. Stratifying patients according to risk of opioid abuse remains a challenge. Preventing misuse/recreational use leading to the addiction cycle, improving abstinence/drug substitution (medical-treatment for opioid use disorder, or MOUD) and preventing relapse, overdose, and death remain an important societal and medical goal. One of the major challenges of treating OUD is that there is no ‘one-size-fits-all’ approach. There is currently no methodology to predict which patient will do best with which medication (Bell and Strang, 2019). Data on opioid receptor expression and activity would help clinician in diagnosing and treating opioid use disorder. However, no in vivo non-invasive methods are currently available for measuring the expression and activity of opioid receptors. SUMMARY In one embodiment, the disclosure provides at least one probe that specifically binds to an opioid receptor (OR) in a subject, such as a human. In another embodiment, the probe contains the compound of formula (I) or a salt thereof. In one aspect, the salt is a pharmaceutically acceptable salt. In another aspect, the probe is non-antigenic. In another aspect, the amount of the probe does not cause significant toxic side effect and is safe for human. In one embodiment, the disclosure provides a composition including compound of formula (I) or a salt thereof. This compound of Formula (I) is a novel fluorescent peptide (also referred to as [Lys7]dermorphin-IRDye800CW or DRM-800). In another embodiment, the composition also contains a carrier. In some embodiments, the carrier is a pharmaceutically acceptable carrier. In another embodiment, the compound is prepared by solid phase peptide synthesis (SPPS) or by recombinant DNA methods. In another embodiment, the compound is prepared by an Fmoc-based solid-phase peptide synthesis (SPPS). In one embodiment, the disclosed compositions and methods may be used to measure occupancy level of the opioid receptor in vivo in a subject by using the non-invasive methods described herein. In another embodiment, the disclosed compositions and methods may be used to measure occupancy level of the opioid receptor in vitro by using a sample taken from the subject. In some aspects, the disclosure provides a method of determining occupancy level of an opioid receptor in a subject, including the steps of: (a) contacting at least one probe with the subject, wherein the probe binds specifically to the opioid receptor (OR) (b) measuring intensity of fluorescent signal emitted by the probe from inner ear of the subject; and (c) determining the occupancy level of the opioid receptor in the subject based on the fluorescence intensity. In one embodiment, the opioid receptor is mu opioid receptor. In one embodiment, step (b) above is performed non-invasively. In another embodiment, fluorescence intensity in spiral ganglion is measured in step (b). In another embodiment, fluorescence intensity is measured by using an oto-spectroscope. In one embodiment, one probe is used. In another embodiment, two or more different probes are used simultaneously. In one aspect, the excitation wavelength used in step (b) ranges between 635 nm and 760 nm. In another aspect, the excitation wavelength is at or about 635 nm. In another aspect, the excitation wavelength is at or about 760 nm. In another aspect, two or more different excitation wavelengths are used simultaneously or sequentially. In another embodiment, occupancy level of the opioid receptor in the subject is calculated quantitatively in step (c). In another embodiment, higher fluorescence intensity indicates lower occupancy level of the opioid receptor. In another embodiment, the probe binds to the opioid receptor and is internalized inside the cells