Radiosynthesis and PET Bioimaging of 76Br-Bedaquiline in a Murine Model of Tuberculosis

Alvaro A. Ordonez, Laurence S. Carroll, Sudhanshu Abhishek, Filipa Mota, Camilo A. Ruiz-Bedoya, Mariah H. Klunk, Alok K. Singh, Joel S. Freundlich, Ronnie C. Mease, Sanjay K. Jain

Research output: Contribution to journalArticle

Abstract

Bedaquiline is a promising drug against tuberculosis (TB), but limited data are available on its intralesional pharmacokinetics. Moreover, current techniques rely on invasive tissue resection, which is difficult in humans and generally limited even in animals. In this study, we developed a novel radiosynthesis for 76Br-bedaquiline and performed noninvasive, longitudinal whole-body positron emission tomography (PET) in live, Mycobacterium tuberculosis-infected mice over 48 h. After the intravenous injection, 76Br-bedaquiline distributed to all organs and selectively localized to adipose tissue and liver, with excellent penetration into infected lung lesions (86%) and measurable penetration into the brain parenchyma (15%). Ex vivo high resolution, two-dimensional autoradiography, and same section hematoxylin/eosin and immunofluorescence provided detailed intralesional drug biodistribution. PET bioimaging and high-resolution autoradiography are novel techniques that can provide detailed, multicompartment, and intralesional pharmacokinetics of new and existing TB drugs. These technologies can significantly advance efforts to optimize drug dosing.

Original languageEnglish (US)
JournalACS Infectious Diseases
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

bedaquiline
Positron-Emission Tomography
Tuberculosis
Autoradiography
Pharmaceutical Preparations
Pharmacokinetics
Hematoxylin
Eosine Yellowish-(YS)
Mycobacterium tuberculosis
Intravenous Injections
Fluorescent Antibody Technique
Adipose Tissue
Technology
Lung
Liver
Brain

Keywords

  • autoradiography
  • PET
  • pharmacokinetics
  • pulmonary
  • TB meningitis

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Radiosynthesis and PET Bioimaging of 76Br-Bedaquiline in a Murine Model of Tuberculosis. / Ordonez, Alvaro A.; Carroll, Laurence S.; Abhishek, Sudhanshu; Mota, Filipa; Ruiz-Bedoya, Camilo A.; Klunk, Mariah H.; Singh, Alok K.; Freundlich, Joel S.; Mease, Ronnie C.; Jain, Sanjay K.

In: ACS Infectious Diseases, 01.01.2019.

Research output: Contribution to journalArticle

Ordonez, Alvaro A. ; Carroll, Laurence S. ; Abhishek, Sudhanshu ; Mota, Filipa ; Ruiz-Bedoya, Camilo A. ; Klunk, Mariah H. ; Singh, Alok K. ; Freundlich, Joel S. ; Mease, Ronnie C. ; Jain, Sanjay K. / Radiosynthesis and PET Bioimaging of 76Br-Bedaquiline in a Murine Model of Tuberculosis. In: ACS Infectious Diseases. 2019.
@article{e1c65271c7ed40cc85c517725e54aa7a,
title = "Radiosynthesis and PET Bioimaging of 76Br-Bedaquiline in a Murine Model of Tuberculosis",
abstract = "Bedaquiline is a promising drug against tuberculosis (TB), but limited data are available on its intralesional pharmacokinetics. Moreover, current techniques rely on invasive tissue resection, which is difficult in humans and generally limited even in animals. In this study, we developed a novel radiosynthesis for 76Br-bedaquiline and performed noninvasive, longitudinal whole-body positron emission tomography (PET) in live, Mycobacterium tuberculosis-infected mice over 48 h. After the intravenous injection, 76Br-bedaquiline distributed to all organs and selectively localized to adipose tissue and liver, with excellent penetration into infected lung lesions (86{\%}) and measurable penetration into the brain parenchyma (15{\%}). Ex vivo high resolution, two-dimensional autoradiography, and same section hematoxylin/eosin and immunofluorescence provided detailed intralesional drug biodistribution. PET bioimaging and high-resolution autoradiography are novel techniques that can provide detailed, multicompartment, and intralesional pharmacokinetics of new and existing TB drugs. These technologies can significantly advance efforts to optimize drug dosing.",
keywords = "autoradiography, PET, pharmacokinetics, pulmonary, TB meningitis",
author = "Ordonez, {Alvaro A.} and Carroll, {Laurence S.} and Sudhanshu Abhishek and Filipa Mota and Ruiz-Bedoya, {Camilo A.} and Klunk, {Mariah H.} and Singh, {Alok K.} and Freundlich, {Joel S.} and Mease, {Ronnie C.} and Jain, {Sanjay K.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1021/acsinfecdis.9b00207",
language = "English (US)",
journal = "ACS Infectious Diseases",
issn = "2373-8227",
publisher = "American Chemical Society",

}

TY - JOUR

T1 - Radiosynthesis and PET Bioimaging of 76Br-Bedaquiline in a Murine Model of Tuberculosis

AU - Ordonez, Alvaro A.

AU - Carroll, Laurence S.

AU - Abhishek, Sudhanshu

AU - Mota, Filipa

AU - Ruiz-Bedoya, Camilo A.

AU - Klunk, Mariah H.

AU - Singh, Alok K.

AU - Freundlich, Joel S.

AU - Mease, Ronnie C.

AU - Jain, Sanjay K.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Bedaquiline is a promising drug against tuberculosis (TB), but limited data are available on its intralesional pharmacokinetics. Moreover, current techniques rely on invasive tissue resection, which is difficult in humans and generally limited even in animals. In this study, we developed a novel radiosynthesis for 76Br-bedaquiline and performed noninvasive, longitudinal whole-body positron emission tomography (PET) in live, Mycobacterium tuberculosis-infected mice over 48 h. After the intravenous injection, 76Br-bedaquiline distributed to all organs and selectively localized to adipose tissue and liver, with excellent penetration into infected lung lesions (86%) and measurable penetration into the brain parenchyma (15%). Ex vivo high resolution, two-dimensional autoradiography, and same section hematoxylin/eosin and immunofluorescence provided detailed intralesional drug biodistribution. PET bioimaging and high-resolution autoradiography are novel techniques that can provide detailed, multicompartment, and intralesional pharmacokinetics of new and existing TB drugs. These technologies can significantly advance efforts to optimize drug dosing.

AB - Bedaquiline is a promising drug against tuberculosis (TB), but limited data are available on its intralesional pharmacokinetics. Moreover, current techniques rely on invasive tissue resection, which is difficult in humans and generally limited even in animals. In this study, we developed a novel radiosynthesis for 76Br-bedaquiline and performed noninvasive, longitudinal whole-body positron emission tomography (PET) in live, Mycobacterium tuberculosis-infected mice over 48 h. After the intravenous injection, 76Br-bedaquiline distributed to all organs and selectively localized to adipose tissue and liver, with excellent penetration into infected lung lesions (86%) and measurable penetration into the brain parenchyma (15%). Ex vivo high resolution, two-dimensional autoradiography, and same section hematoxylin/eosin and immunofluorescence provided detailed intralesional drug biodistribution. PET bioimaging and high-resolution autoradiography are novel techniques that can provide detailed, multicompartment, and intralesional pharmacokinetics of new and existing TB drugs. These technologies can significantly advance efforts to optimize drug dosing.

KW - autoradiography

KW - PET

KW - pharmacokinetics

KW - pulmonary

KW - TB meningitis

UR - http://www.scopus.com/inward/record.url?scp=85070587387&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070587387&partnerID=8YFLogxK

U2 - 10.1021/acsinfecdis.9b00207

DO - 10.1021/acsinfecdis.9b00207

M3 - Article

C2 - 31345032

AN - SCOPUS:85070587387

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

SN - 2373-8227

ER -