Synthesis,⁶⁸Ga-Radiolabeling, and PreliminaryIn VivoAssessment 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 67/68Ga-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.

Preclinical assessment of 68Ga‐PSMA‐617 entrapped in a microemulsion delivery system for applications in prostate cancer PET/CT imaging

“…Quality control of [ 68 Ga]Ga‐PSMA‐617 followed previously published described methods for high performance liquid chromatography (HPLC) and instant‐thin layer chromatography (ITLC) . A reverse‐phase HPLC column (Zorbax StableBond C18, 0.46 × 2 cm × 5 μm; Agilent Technologies, CA, USA) performing gradient elution (5%‐95% A‐B over 15 minutes) at a flow rate of 1 mL/min was employed (Solvent A = 0.1% aqueous trifluoroacetic acid [TFA]; solvent B = 0.1% TFA in acetonitrile).…”

An update on radiotracer development for molecular imaging of bacterial infections

“…Depsidomycin itself is a natural AMP isolated from S. lavendofolae and exhibits antimicrobial activities against i.e., drug-resistant M. tuberculosis [80]. As a tracer, 68 Ga-DOTA-TBIA101 detected muscular E. coli infections in mice with abscessto-muscle ratios between 1.2 and 1.6 [81], S. aureus (with a target-to-nontarget ratio between 1.2 and 1.3), and M. tuberculosis (abscess-to-muscle ratios between 2.0 and 2.8) infections in rabbits [82]. These results indicate a preference for infections with M. tuberculosis, but unfortunately the tracer also accumulated at sites of sterile inflammation which limits its translational potential.…”

Preclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic Infection Imaging Agent

“…Our pilot study reports the depsipeptide synthesis of NH 2 - l -Proline- l -Leucine- l -Proline- l -Valine- l -Leucine- l -Thronine- l -Isolleucine-OH (TBIA101), and successful DOTA conjugation using a bi- l -Glycine-linker ( Figure 2 ) which was introduced to prevent DOTA from affecting any hydrogen bonding with the peptides backbone that could influence the natural configuration of TBIA101. Additionally, we succeeded in radiolabeling DOTA-TBIA101 with 68 Ga, which allowed for PET/CT imaging in targeting myositis in Escherichia coli infected mice [ 27 ]; however, no further preclinical evaluation was possible using this model.…”