[68Ga]Ga-DOTA-DP-UBI 29-41: A Novel 68Ga-Labeled Ubiquicidin 29-41 Derivative Containing d-Proline for Bacterial Infection PET Imaging

Abstract

Bacterial infection poses a persistent and severe threat to human health. Accurate differentiation between bacterial infection and sterile inflammation is critical for timely clinical treatment. In this study, a novel ⁶⁸Ga-labeled radiotracer ([⁶⁸Ga]Ga-DOTA-DP-UBI 29-41) was radiosynthesized by labeling the UBI 29-41 derivative (DOTA-DP-UBI 29-41) with ⁶⁸Ga. This radiotracer was designed by introducing d-proline (DP) as a linker between the ubiquicidin 29-41 (UBI 29-41) targeting segment and the 1,4,7,10-tetraazacyclododecane-N,N′,N,N′-tetraacetic acid (DOTA) chelating group. The radiotracer exhibited high radiochemical purity (RCP > 98%) and favorable in vitro stability in normal saline at room temperature and mouse serum at 37 °C, with hydrophilic properties (LogD = −3.58 ± 0.04). In vitro bacterial experiments confirmed the specific and rapid binding of this radiotracer to Staphylococcus aureus, with binding reaching equilibrium within 30 min of incubation and exhibiting concentration-dependent competitive inhibition with UBI 29-41. Biodistribution studies in mouse models revealed effective accumulation of the tracer at bacterial infection sites (1.98 ± 0.66% ID/g at 30 min p.i.), significantly lower renal uptake (stabilized at ∼25% ID/g) than previous ⁶⁸Ga-labeled UBI 29-41 derivatives, and a distinct difference in uptake between bacterium-infected and sterile inflamed muscles (an infection-to-inflammation ratio of 2.11 at 120 min p.i.). PET/CT imaging further confirmed that the tracer could clearly visualize bacterial infection foci and distinguish infection from sterile inflammation in dual-pathology mice, with rapid blood clearance kinetics, renal metabolism, and excretion. Collectively, these results indicate that [⁶⁸Ga]Ga-DOTA-DP-UBI 29-41 will be a promising PET tracer for the specific diagnosis of bacterial infection and differentiation from sterile inflammation.