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

Abstract

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.

• Authors: Thomas Ebenhan, Jan Rijn Zeevaart, Jacobus D Venter, Thavendran Govender, Gert H Kruger, Neil V Jarvis, Mike M Sathekge
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 55 Issue 2 Pg. 308-14 (Feb 2014) ISSN: 1535-5667 [Electronic] United States
• PMID: 24434293 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimicrobial Cationic Peptides
• Gallium Radioisotopes
• Heterocyclic Compounds
• Heterocyclic Compounds, 1-Ring
• Radiopharmaceuticals
• Ribosomal Proteins
• ribosomal protein S30
• 1,4,7-triazacyclononane-N,N',N''-triacetic acid
• Turpentine

Topics

• Animals
• Antimicrobial Cationic Peptides (chemistry)
• Gallium Radioisotopes
• Heterocyclic Compounds (chemistry)
• Heterocyclic Compounds, 1-Ring
• Infections (diagnosis, diagnostic imaging)
• Inflammation
• Lung (drug effects)
• Positron-Emission Tomography (methods)
• Rabbits
• Radiopharmaceuticals
• Ribosomal Proteins (chemistry)
• Staphylococcal Infections (metabolism)
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon (methods)
• Tomography, X-Ray Computed (methods)
• Turpentine (chemistry)