Synthesis, 68Ga-radiolabeling, and preliminary in vivo assessment of a depsipeptide-derived compound as a potential PET/CT infection imaging agent.

Botshelo B Mokaleng,Suhas Ramesh,Puja P Hazari,Anil K Mishra,Hendrik G Kruger,Jan R Zeevaart,Thomas Ebenhan,Mike M Sathekge,Biljana Marjanovic-Painter,Thavendran Govender,Raveen Parboosing

doi:10.1155/2015/284354

Abstract

Noninvasive imaging is a powerful tool for early diagnosis and monitoring of various disease processes, such as infections. An alarming shortage of infection-selective radiopharmaceuticals exists for overcoming the diagnostic limitations with unspecific tracers such as 67/68Ga-citrate or 18F-FDG. We report here TBIA101, an antimicrobial peptide derivative that was conjugated to DOTA and radiolabeled with 68Ga for a subsequent in vitro assessment and in vivo infection imaging using Escherichia coli-bearing mice by targeting bacterial lipopolysaccharides with PET/CT. Following DOTA-conjugation, the compound was verified for its cytotoxic and bacterial binding behaviour and compound stability, followed by 68Gallium-radiolabeling. µPET/CT using 68Ga-DOTA-TBIA101 was employed to detect muscular E. coli-infection in BALB/c mice, as warranted by the in vitro results. 68Ga-DOTA-TBIA101-PET detected E. coli-infected muscle tissue (SUV = 1.3–2.4) > noninfected thighs (P = 0.322) > forearm muscles (P = 0.092) > background (P = 0.021) in the same animal. Normalization of the infected thigh muscle to reference tissue showed a ratio of 3.0 ± 0.8 and a ratio of 2.3 ± 0.6 compared to the identical healthy tissue. The majority of the activity was cleared by renal excretion. The latter findings warrant further preclinical imaging studies of greater depth, as the DOTA-conjugation did not compromise the TBIA101's capacity as targeting vector.

Highlights

Radiopharmaceuticals are a powerful tool in managing patients with infectious diseases
Because some antimicrobial peptides (AMP) selectively target structures of the bacterial cell wall envelope, they have recently been investigated; preliminary data has suggested that these AMP have the potential to distinguish infection from aseptic inflammation [2, 3]. 99mTc-UBI29-41 has been shown to have the ability to detect bacterial infection using SPECT in clinical trials [4] but an increase in the availability and accessibility of PET/CT facilities has sparked renewed interest in generator-based PET radiopharmaceuticals
We report in this paper the preliminary findings of the antimicrobial in vitro behaviour of 68Ga-DOTA-TBIA101 and its potential for targeting infection with noninvasive imaging in an E. coli-bearing mice model

Summary

Introduction

Radiopharmaceuticals are a powerful tool in managing patients with infectious diseases. Discerning infection from sterile inflammation is still one of the most common problems in nuclear medicine. For this reason several radiopharmaceuticals have been studied to find the solution to this difficult situation. BioMed Research International radiopharmaceuticals, such as labeled leucocytes, Gallium67- (67Ga-) citrate, Indium-111- (111In-) IgG, Technetium99m- (99mTc-) labeled ciprofloxacin, and Flouride-18- (18F-) FDG may result in false-positive diagnostics and, in some cases, a definite differential diagnosis between infection and aseptic inflammation cannot be achieved [1, 2]. 99mTc-UBI29-41 has been shown to have the ability to detect bacterial infection using SPECT in clinical trials [4] but an increase in the availability and accessibility of PET/CT facilities has sparked renewed interest in generator-based PET radiopharmaceuticals. The approach using 68GaNOTA-UBI29-41 motivated for the strategy, that specific short peptides make perfect vector molecules to detect bacteria if joined by a suitable 68Ga-carrier molecule such as DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) without compromising the compounds targeting capacity

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