Caspase-Based PET for Evaluating Pro-Apoptotic Treatments in a Tuberculosis Mouse Model

Area of Science:

• Biomedical Imaging
• Molecular Imaging
• Radiochemistry

Background:

• Tuberculosis (TB) remains a significant global health challenge, with Mycobacterium tuberculosis evading host defenses by preventing macrophage apoptosis.
• This evasion leads to necrosis, hindering antimicrobial penetration and treatment efficacy.
• Host-directed therapies (HDTs) targeting apoptosis offer a promising strategy to enhance TB treatment.

Purpose of the Study:

• To evaluate [¹⁸F]-ICMT-11, a novel PET radiotracer, as a tool to measure pro-apoptotic activity in a preclinical model of pulmonary tuberculosis.
• To assess the utility of [¹⁸F]-ICMT-11 in conjunction with pro-apoptotic drugs for TB treatment.

Main Methods:

• Utilized macrophage cell cultures and a murine model of pulmonary TB.
• Administered [¹⁸F]-ICMT-11, a caspase-3/7-specific PET tracer, to assess apoptosis.
• Correlated tracer uptake with caspase-3/7 activity and treatment response.

Main Results:

• [¹⁸F]-ICMT-11 uptake was significantly higher in M. tuberculosis-infected cells and tissues treated with cisplatin, correlating with increased caspase-3/7 activity.
• PET imaging revealed higher [¹⁸F]-ICMT-11 signals in infected mice treated with cisplatin compared to untreated controls.
• The tracer effectively detected intralesional pro-apoptotic responses in situ.

Conclusions:

• [¹⁸F]-ICMT-11 PET imaging provides a noninvasive method for assessing intralesional pro-apoptotic responses in pulmonary TB.
• This PET tracer can aid in the development and evaluation of pro-apoptotic host-directed therapies for tuberculosis.
• The findings support the potential of [¹⁸F]-ICMT-11 as a valuable tool in TB research and drug development.