Dynamic 18F-Pretomanid PET imaging reveals excellent brain penetration in animal models of TB meningitis and first-in-human studies

Abstract Pretomanid is a nitroimidazole antimicrobial with potent activity against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) for the treatment of multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of pretomanid into privileged sites such as the brain, as well as the efficacy of the BPaL regimen for TB meningitis, remain unknown. Importantly, there are no well accepted treatments for TB meningitis due to MDR strains, resulting in high mortality. We developed a new synthetic route to obtain 18F-pretomanid (chemically identical to the parent antibiotic) and performed cross-species positron emission tomography (PET) imaging to noninvasively measure intralesional pretomanid concentration-time profiles in the central nervous system (CNS). Dynamic PET in mouse and rabbit models of TB meningitis demonstrated excellent CNS penetration of pretomanid. Antibiotic levels were spatially compartmentalized and cerebrospinal fluid (CSF) levels did not correlate with those in the brain parenchyma. Post-mortem autoradiography and mass spectrometry corroborated the imaging findings. The bactericidal activity of the BPaL regimen in the mouse model of TB meningitis was substantially inferior to the standard TB regimen, likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Finally, first-in-human dynamic 18F-pretomanid PET in six healthy volunteers demonstrated excellent penetration of pretomanid into the CNS, with significantly higher levels in the brain parenchyma versus CSF (P < 0.01). These data have important implications for developing new antibiotic treatments for TB meningitis.