title: Synthesis, 68Ga-radiolabeling, and preliminary in vivo assessment of a depsipeptide-derived compound as a potential PET/CT infection imaging agent.
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 (67/68)Ga-citrate or (18)F-FDG. We report here TBIA101, an antimicrobial peptide derivative that was conjugated to DOTA and radiolabeled with (68)Ga 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 (68)Gallium-radiolabeling. µPET/CT using (68)Ga-DOTA-TBIA101 was employed to detect muscular E. coli-infection in BALB/c mice, as warranted by the in vitro results. (68)Ga-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.
authors.affiliation: Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Corner Malherbe and Steve Biko Road, Pretoria 0001, South Africa.
authors.forename: Botshelo B
authors.initials: BB
authors.lastname: Mokaleng
authors.affiliation: Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Corner Malherbe and Steve Biko Road, Pretoria 0001, South Africa ; School of Chemistry and Physics, Westville Campus, University Road, Westville, Durban 3630, South Africa.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebenhan
authors.affiliation: School of Health Sciences, Catalysis and Peptide Research Unit, E-Block 6th Floor, Westville Campus, University Road, Westville, Durban 3630, South Africa.
authors.forename: Suhas
authors.initials: S
authors.lastname: Ramesh
authors.affiliation: School of Health Sciences, Catalysis and Peptide Research Unit, E-Block 6th Floor, Westville Campus, University Road, Westville, Durban 3630, South Africa.
authors.forename: Thavendran
authors.initials: T
authors.lastname: Govender
authors.affiliation: School of Health Sciences, Catalysis and Peptide Research Unit, E-Block 6th Floor, Westville Campus, University Road, Westville, Durban 3630, South Africa.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Kruger
authors.affiliation: Department of Virology, University of KwaZulu-Natal, National Health Laboratory Service, P.O. Box 1900, Westville, Durban 3630, South Africa.
authors.forename: Raveen
authors.identifier: 0000-0002-5476-1011
authors.initials: R
authors.lastname: Parboosing
authors.affiliation: Division of PET Imaging & Radiochemistry, Molecular Imaging Research Centre, INMAS, Brig S. K. Mazumdar Marg, Timarpur, Delhi 110054, India.
authors.forename: Puja P
authors.initials: PP
authors.lastname: Hazari
authors.affiliation: Division of PET Imaging & Radiochemistry, Molecular Imaging Research Centre, INMAS, Brig S. K. Mazumdar Marg, Timarpur, Delhi 110054, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mishra
authors.affiliation: Radiochemistry Section Necsa, Building P1600, Pelindaba, Brits, North West Province, South Africa.
authors.forename: Biljana
authors.initials: B
authors.lastname: Marjanovic-Painter
authors.affiliation: Department of Science and Technology, Preclinical Drug Development Platform, North West University, 11 Hoffman Street, Potchefstroom 2520, South Africa.
authors.forename: Jan R
authors.initials: JR
authors.lastname: Zeevaart
authors.affiliation: Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Corner Malherbe and Steve Biko Road, Pretoria 0001, South Africa.
authors.forename: Mike M
authors.initials: MM
authors.lastname: Sathekge
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D047630:Depsipeptides / Q000737:chemistry*; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000175:diagnosis; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry; D005710:Gallium Radioisotopes / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009132:Muscles / Q000382:microbiology; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000737:chemistry*; D014057:Tomography, X-Ray Computed / Q000379:methods
chemical_list: D000890:Anti-Infective Agents; D047630:Depsipeptides; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid