Preclinical evaluation of 68Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-ubiquicidin as a radioligand for PET infection imaging.

UNLABELLED: Antimicrobial peptides such as ubiquicidin (UBI) are believed to differentiate between mammalian and bacterial or fungal cells. (99m)Tc-UBI29-41 was previously tested for detecting infection in humans using SPECT. For the present study, the UBI fragment UBI29-41 (TGRAKRRMQYNRR) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA), radiolabeled with (68)Ga, and investigated in a rabbit infection model. METHODS: (68)Ga was obtained from a 1.85-GBq (68)Ge/(68)Ga generator. New Zealand White rabbits were anesthetized with ketamine/medetomidine before tracer administration and placed in a clinical PET/CT scanner. (68)Ga-1,4,7-triazacyclononane-1,4,7-triacetic-acid-ubiquicidin29-41 ((68)Ga-NOTA-UBI29-41) was formulated in saline solution, and 101 ± 41 MBq were administered intravenously. The tracer distribution was studied by PET/CT imaging in animals (a) that were healthy, (b) bearing muscular Staphylococcus aureus infections and turpentine oil-induced muscular inflammations, and (c) bearing ovalbumin-induced lung inflammations. Static PET/CT imaging was performed at different time intervals up to 120 min after injection. For calculation of target-to-nontarget ratios, standardized uptake values were normalized against healthy thigh muscle, representing nontargeted tissue. RESULTS: PET/CT images of healthy animals showed predominant distribution in the kidneys, liver, and bladder; heart and spleen showed moderate, declining uptake, only. The biologic half-life in blood was 29 min. Urinary accumulation of (68)Ga-NOTA-UBI29-41 peaked at 3.8 ± 0.91 percentage injected dose per gram (%ID) at 120 min, and 88 ± 5.2 %ID was recovered in total urine. (68)Ga-NOTA-UBI29-41 imaging in (b) selectively visualized the muscular infection site and was differentiated from sterile inflammatory processes. Standardized uptake value ratios for muscles (infected/inflamed) were 2.9 ± 0.93, 2.9 ± 0.50, 3.5 ± 0.86, and 3.8 ± 0.90 at 5, 30, 60, and 90 min after injection, respectively. Rabbit lungs with asthma showed insignificant uptake. CONCLUSION: (68)Ga-NOTA-UBI29-41 was strongly localized in bacteria-infected areas and minimally detected in a sterile inflammation area in rabbit muscles. The findings propose this compound to be an excellent first-line PET/CT tracer to allow the distinguishing of infection from inflammation.

Thermodynamic evaluation of the stability of the bone-seeking radiopharmaceutical [177Lu]Lu(III)-DOTP under simulated blood plasma conditions.

The stability and in vivo robustness of [(177)Lu]Lu-DOTP as a potential bone-targeting radiopharmaceutical was determined with the aid of thermodynamic blood plasma modeling simulations. Glass electrode potentiometry was employed to measure the stability constants of the complexes of Lu(3+) with DOTP. Similarly, the complexes of DOTP with a selection of the important physiological metal ions: Ca(2+), Mg(2+), and Cu(2+) were determined, representing the typical interactions that the ligand would encounter upon administration. This made possible the construction of a blood plasma model of DOTP, aiding in establishing the potential susceptibility of the radiopharmaceutical. The ligand binds predominantly to calcium in vivo, accounting for 59.6% of that initially introduced as a component of the Lu-DOTP complex. Furthermore, due to a preference of the DOTP to bind to Cu(2+) it causes mobilization of the ions in blood plasma, and would therefore indicate a deficiency if the ligand is administered at a concentration of 8.5 × 10(-5) mol dm(-3). The lutetium-ions are preferentially bound to DOTP, with as much as 98.1% of the Lu(3+) occupying the ligand under physiological conditions.