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Evaluation of [111In]-Labeled Zinc–Dipicolylamine Tracers for SPECT Imaging of Bacterial Infection

Molecular Imaging and Biology volume 17, pages 204–213 (2015)Cite this article

Abstract

Purpose

This study prepared three structurally related zinc–dipicolylamine (ZnDPA) tracers with [111In] labels and conducted biodistribution and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging studies of a mouse leg infection model.

Procedures

Two monovalent tracers, ZnDPA-[111In]DTPA and ZnDPA-[111In]DOTA, each with a single zinc–dipicolylamine targeting unit, and a divalent tracer, Bis(ZnDPA)-[111In]DTPA, with two zinc–dipicolylamine units were prepared. Organ biodistribution and SPECT and CT imaging studies were performed on living mice with a leg infection created by injection of clinically relevant Gram positive Streptococcus pyogenes. Fluorescent and luminescent Eu3+-labeled versions of these tracers were also prepared and used to measure relative affinity for the exterior membrane surface of bacterial cells and mimics of healthy mammalian cells.

Results

All three 111In-labeled radiotracers were prepared with a radiopurity of >90 %. The biodistribution studies showed that the two monovalent tracers were cleared from the body through the liver and kidney, with retained percentage injected dose for all organs of <8 % at 20 h and infected leg target to non-target ratio (T/NT) ratio of ≤3.0. Clearance of the divalent tracer from the bloodstream was slower and primarily through the liver, with a retained percentage injected dose for all organs <37 % at 20 h and T/NT ratio rising to 6.2 after 20 h. The SPECT/CT imaging indicated the same large difference in tracer pharmacokinetics and higher accumulation of the divalent tracer at the site of infection.

Conclusions

All three [111In]-ZnDPA tracers selectively targeted the site of a clinically relevant mouse infection model that could not be discerned by visual external inspection of the living animal. The highest target selectivity, observed with a divalent tracer equipped with two zinc–dipicolylamine targeting units, compares quite favorably with the imaging selectivities previously reported for other nuclear tracers that target bacterial cell surfaces. The tracer pharmacokinetics depended heavily on tracer molecular structure suggesting that it may be possible to rapidly fine tune the structural properties for optimized in vivo imaging performance and clinical translation.

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Abbreviations

DPPE-PEG2000 :

1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt)

POPC:

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine

ZnDPA:

zinc–dipicolylamine

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Acknowledgments

We are grateful for funding support from NIH grants RO1GM059078 (B. D. S.) and T32GM075762 (D. R. R.), and the Notre Dame Integrated Imaging Facility (NDIIF).

Conflict of Interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA

    Douglas R. Rice, Adam J. Plaunt, Serhan Turkyilmaz & Bradley D. Smith

  2. Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, Worcester, MA, 01655, USA

    Miles Smith, Yuzhen Wang & Mary Rusckowski

Authors
  1. Douglas R. Rice
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  2. Adam J. Plaunt
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  3. Serhan Turkyilmaz
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  7. Bradley D. Smith
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Correspondence to Bradley D. Smith.

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Rice, D.R., Plaunt, A.J., Turkyilmaz, S. et al. Evaluation of [111In]-Labeled Zinc–Dipicolylamine Tracers for SPECT Imaging of Bacterial Infection. Mol Imaging Biol 17, 204–213 (2015). https://doi.org/10.1007/s11307-014-0758-8

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Key words

  • Zinc–dipicolylamine
  • Infection imaging
  • SPECT/CT
  • 111-indium
  • Molecular tracer