Abstract

The diagnosis of infectious diseases continues to challenge clinicians, particularly when it comes to distinguishing active infection from sterile inflammation or malignant processes. Traditional imaging modalities, while invaluable, often lack the specificity required for precise infection localization. Recent research has focused on antimicrobial peptides as potential infection-specific radiopharmaceuticals. Among these, ubiquicidin (29–41), a synthetic fragment derived from the antimicrobial peptide ubiquicidin, has emerged as a promising tracer. Radiolabeled ubiquicidin (29–41), particularly with technetium-99m, has demonstrated rapid, specific accumulation at sites of infection, while showing minimal uptake in sterile inflammation. This review outlines the molecular basis of ubiquicidin’s action, summarizes preclinical and clinical studies, and highlights its comparative advantages, current limitations, and future prospects as an infection imaging agent.

1. Introduction

Infectious diseases remain a leading cause of morbidity and mortality worldwide, accounting for millions of deaths annually despite advances in antimicrobial therapy. Rapid and accurate diagnosis is crucial, not only for guiding treatment but also for limiting antimicrobial resistance through targeted therapy. Conventional imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound provide excellent anatomical detail but often fail to distinguish infection from non-infectious processes. Functional imaging modalities using radiopharmaceuticals, including 67Ga-citrate scintigraphy, 111In-labeled leukocyte imaging, and 18F-fluorodeoxyglucose (FDG)-PET, have provided additional diagnostic tools. However, limitations persist: FDG is taken up by both infection and sterile inflammation, leukocyte labeling is labor-intensive, and 67Ga offers poor resolution. Thus, there is a growing need for tracers with true infection specificity.

2. Ubiquicidin and the Synthetic Fragment UBI (29–41)

Ubiquicidin is a cationic antimicrobial peptide originally isolated from the cytoplasmic granules of neutrophils. Its natural function is to bind bacterial membranes, which are characteristically rich in negatively charged phospholipids, thereby disrupting their integrity. This intrinsic microbial affinity sparked interest in its use as an infection-targeting probe. The synthetic fragment ubiquicidin (29–41) represents a 13-amino acid stretch with preserved bacterial affinity and enhanced in vivo stability. Unlike the full-length peptide, UBI (29–41) is less prone to proteolytic degradation, making it more suitable for radiopharmaceutical development. Its net positive charge promotes selective binding to bacteria over mammalian cells, enabling infection-specific imaging.

3. Radiolabeling Approaches

The majority of studies have utilized technetium-99m (99mTc) for labeling UBI (29–41). The choice is logical: 99mTc is inexpensive, readily available from hospital generators, and offers favorable imaging properties (140 keV gamma emission, 6-hour half-life). Radiolabeling can be performed rapidly using direct methods, producing a stable complex without significant loss of biological activity. Other isotopes have been investigated to expand UBI’s applications. Gallium-68 (68Ga) labeling enables positron emission tomography (PET), offering higher spatial resolution and quantitative capabilities. Fluorine-18 (18F) and copper-64 (64Cu) analogues are also being explored, broadening potential clinical utility.

4. Preclinical Studies

Animal studies have been crucial in establishing the infection-specific profile of UBI (29–41). Welling et al. (2000) reported that 99mTc-labeled UBI (29–41) accumulated rapidly and specifically at sites of bacterial infection in murine models, showing high target-to-background ratios and minimal uptake in sterile inflammatory lesions. Biodistribution studies highlighted favorable pharmacokinetics: rapid blood clearance, minimal hepatic or intestinal accumulation, and predominant renal excretion. Importantly, UBI (29–41) displayed no significant binding to mammalian cells or non-infectious inflammatory tissue, underscoring its diagnostic promise. Other investigations extended these observations to fungal and multidrug-resistant bacteria, suggesting a broad-spectrum imaging potential.

5. Clinical Investigations

First-in-human trials provided encouraging results. Akhtar et al. (2005) evaluated 99mTc-UBI (29–41) in patients with suspected bone, soft tissue, and prosthetic joint infections. Imaging showed rapid uptake at infectious sites within 30–60 minutes post-injection, with low background activity. Sensitivity exceeded 90%, while specificity remained superior to conventional scintigraphic agents. Further clinical studies confirmed safety and tolerability, with no adverse reactions reported. Melendez-Alafort and colleagues demonstrated that 99mTc-UBI (29–41) could differentiate infection from sterile inflammation, outperforming 67Ga-citrate and offering faster, clearer results. Small case series also reported utility in diabetic foot infections, osteomyelitis, and endocarditis, expanding its clinical relevance.

6. Comparative Advantages

Compared to traditional agents, UBI (29–41) offers several notable advantages: (1) High specificity: Binds directly to bacterial membranes, reducing false positives from sterile inflammation. (2) Rapid imaging: Diagnostic-quality scans can be obtained within 1–2 hours, compared to 24–48 hours for 111In-labeled leukocytes. (3) Ease of preparation: Simple labeling protocols with 99mTc generators, suitable for routine hospital use. (4) Low toxicity: No reported immunogenic or toxic effects in clinical studies. These features position UBI (29–41) as a superior infection-targeting probe compared to FDG-PET and traditional scintigraphy.

7. Limitations and Challenges

Despite its promise, UBI (29–41) faces hurdles before widespread adoption. Most clinical studies involve small cohorts; multicenter trials are required to establish efficacy across diverse populations. Peptide-based radiopharmaceuticals may incur higher production costs compared to small-molecule tracers, raising economic considerations. Standardization of labeling protocols across institutions remains a technical challenge. Additionally, while specificity is superior, FDG-PET remains widely available and entrenched in clinical workflows, representing a formidable competitor. Regulatory approval pathways also require robust, reproducible evidence of efficacy and safety.

8. Future Directions

Research continues to optimize UBI (29–41) and expand its applications. PET imaging with 68Ga-UBI offers the promise of higher-resolution infection imaging, particularly valuable for deep-seated or small lesions. Novel strategies aim to develop theranostic applications, combining diagnostic imaging with antimicrobial activity. Expanding investigations into fungal, mycobacterial, and multidrug-resistant pathogens could broaden clinical indications. Furthermore, use in immunocompromised patients—where leukocyte-based imaging is unreliable—represents a particularly promising direction. Integration with hybrid modalities such as PET/MRI may enhance diagnostic performance and clinical adoption.

9. Conclusion

Ubiquicidin (29–41) represents a new frontier in infection imaging. Its unique bacterial specificity, favorable pharmacokinetics, and ease of radiolabeling make it a compelling alternative to conventional tracers. While larger clinical trials and regulatory validation are essential, current evidence supports its role as an emerging agent capable of transforming the diagnostic approach to infectious diseases. The next decade will likely determine whether UBI (29–41) secures a permanent place in the clinical armamentarium.

References

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2. Akhtar MS, Iqbal J, Khan ME, Irfanullah J, Jehangir M, Khan B, et al. In vivo evaluation of 99mTc-ubiquicidin (29–41) as a potential infection imaging agent. Eur J Nucl Med Mol Imaging. 2005;32(11):1292–1300.

3. Melendez-Alafort L, Arteaga de Murphy C, Herrera-Rodriguez R, et al. 99mTc-ubiquicidin [29–41] as a radiopharmaceutical for the diagnosis of infectious diseases. Nucl Med Commun. 2004;25(11):1091–1097.

4. Nibbering PH, Welling MM, Paulusma-Annema A, et al. Radiolabeled antimicrobial peptides for infection detection. Lancet Infect Dis. 2004;4(12):794–803.