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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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111In-DPC11870

111In-DPC11870
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894

Created: ; Last Update: December 19, 2008.

Chemical name:111In-DPC11870image 24711511 in the ncbi pubchem database
Abbreviated name:111In-DPC11870
Synonym:Divalent DTPA-conjugated LTB4 antagonist 17
Agent Category:Compound
Target:Leukotriene B4 receptor
Target Category:Receptor
Method of detection:Single photon emission computed tomography (SPECT); Planar gamma imaging
Source of signal / contrast:111In
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.

Background

[PubMed]]

The mobilization and activation of leukocytes during an inflammatory response is mediated through the binding of leukotriene B4 (LTB4) to its receptor on the membrane of these cells. On the basis of affinity, there are two known types of LTB4 receptors, BLT1 and BLT2 (1, 2). The BLT1 receptor is of the high-affinity type and is found primarily on neutrophils, and the BLT2 receptor is of the low-affinity variety that is found on most nucleated blood cells. Binding of LTB4 to the BLT receptors leads to chemotaxis and chemokinesis, which result in activation of granulocytes and macrophages as a response to inflammation and infection. Therefore, radiolabeled autologous leukocytes can be used for the detection and imaging of infection and inflammation. However, this in vitro process may require handling of contaminated blood, which puts the handler at risk for blood-borne infection. Investigators are in search of a radiochemical that would be convenient to handle and easy to prepare for the detection of infection and inflammation (3). In this regard, a variety of radiolabeled peptides and antibodies targeted toward specific receptors are now available for the diagnosis and imaging of infection and inflammation (4).

Because leukotrienes have an important role in the mediation of attraction and infiltration of granulocytes toward the sites of infection and inflammation, an LTB4 antagonist, 111indium (111In)-labeled DPC11870, has been investigated for potential scintigraphic imaging of these conditions (5). 111In-DPC11870 has been shown to bind to the BLT receptors on hematopoietic cells that accumulate at the site of infection in rabbits and could be used for imaging of the lesions (6).

Synthesis

[PubMed]

The synthesis of 111In-DPC11870 has been detailed by van Eerd et al. (7). Briefly, 111In-DPC11870 synthesis was based on a polyethylene glycol derivative of SG385, another LTB4 antagonist (8). Blocked cysteic acid (boc-cysteic acid) and Glu(OTfp)-OTfp were prepared as described previously (9, 10). The tetra-cysteic acid derivative of SG385 was prepared by sequential addition of boc-cysteic acid in dimethylformamide to the benzotriazol-tetramethyluronium-hexafluorophosphate coupling reagent. The block was removed with a 50:50 trifluoroacetic acid:methylene chloride treatment and purification was performed by high-performance liquid chromatography (HPLC) on a C18 silica column after addition of the first, second, and fourth cysteic acids. The tetra-cysteic acid derivative product 11870 was recovered after HPLC by lyophilization and checked by HPLC and high-resolution mass spectroscopy. Dimerization of 11870 was achieved by a reaction of 11870 with bis-trifluoropropanone ester of blocked glutamic acid and hydroxyazabenzotriazole in dimethylformamide. The crude reaction product was treated with a combination of trifluoroacetic acid, methylene chloride, and triethylsilane to remove the remaining blocking group. The product was purified on a C18 column by HPLC. Conjugation with diethylenetriaminepentaacetic acid was performed by a reaction of diethylenetriaminepentaacetic acid anhydride in dimethylformamide. The final yield of unlabeled DPC11870 was 73% and HPLC analysis exhibited a single peak.

DPC11870 was labeled with 111In at pH 5.5 in ammonium acetate buffer for 30 min at room temperature. Radiochemical purity of the product as determined by instant thin-layer chromatography and reverse-phase HPLC was >99%, and the specific activity was 0.32 mCi/nmol (12 MBq/nmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]]

Using purified human granulocytes, the 50% inhibitory concentration (IC50) of 111In-DPC11870 was determined to be 10 nmol/L. In the presence of nonradioactive DPC11870, the radiochemical had high (40%) nonspecific binding but showed very low binding (<5%) to lymphocytes and erythrocytes (3).

Animal Studies

Rodents

[PubMed]

To evaluate the use of 111In-DPC11870 for the visualization of infection in rabbits, the animals were given an intramuscular injection of Escherichia coli (3). Twenty-four hours later, when the infection was apparent by swelling, the rabbits were given an intravenous injection of 111In-DPC11870. Some animals received an injection of nonradioactive In-DPC11870 before the radiochemical was administered. This was done to saturate the LTB4 receptors for the determination of receptor-mediated accumulation of 111In-DPC11870. Radioactivity accumulated in the liver, lung, and kidney immediately after injection of the radiochemical and subsequently appeared in the spleen and bone marrow. Visualization of the abscess was observed two hours after injection and the visualization improved with time. Rabbits preinjected with the nonradioactive compound showed no appearance of the label at the site of the abscess, indicating that the abscess uptake of radioactivity was mediated by the receptor.

In another study (6), the abscess was visualized after rabbits were injected with the radiochemical and the E. coli infection was induced 16 h later. Another group of animals that showed signs of infection was administered heterologous leukocytes and bone marrow cells labeled in vitro with 111In-DPC11870. The biodistribution of 111In-DPC11870 was compared in the two groups of animals. An accumulation of radioactivity was observed at the site of the abscess in both groups of animals, confirming that the radioactivity accumulated at the site of infection because of the migration of the activated hematopoietic cells to the site of infection.

111In-DPC11870 was also shown to clearly visualize acute colitis lesions in rabbits less than one hour after injection of the radiolabel (11). The investigators also concluded that images acquired with 111In-DPC11870 were superior to those obtained with either 99mTc-labeled granulocytes or fluorine [18F]FDG.

The use of 111In-DPC11870 to visualize experimentally induced pulmonary aspergillosis in rabbits was evaluated in comparison to 67Ga-citrate (7). Images were acquired 24 h after injection of the radiolabels, and the images obtained with 111In-DPC11870 were determined to be superior to the images obtained with 67Ga-citrate.

Other Non-Primate Mammals

[PubMed]

No publications are currently available.

Non-Human Primates

[PubMed]

No publications are currently available.

Human Studies

[PubMed]

No publications are currently available.

Supplemental Information

[Disclaimers]

No supplemental information is currently available.

References

1.
Yokomizo T., Izumi T., Chang K., Takuwa Y., Shimizu T. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature. 1997;387(6633):620–4. [PubMed: 9177352]
2.
Yokomizo T., Kato K., Terawaki K., Izumi T., Shimizu T. A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J Exp Med. 2000;192(3):421–32. [PMC free article: PMC2193217] [PubMed: 10934230]
3.
van Eerd J.E., Oyen W.J., Harris T.D., Rennen H.J., Edwards D.S., Liu S., Ellars C.E., Corstens F.H., Boerman O.C. A bivalent leukotriene B(4) antagonist for scintigraphic imaging of infectious foci. J Nucl Med. 2003;44(7):1087–91. [PubMed: 12843226]
4.
Signore A., Chianelli M., D'Alessandria C., Annovazzi A. Receptor targeting agents for imaging inflammation/infection: where are we now? Q J Nucl Med Mol Imaging. 2006;50(3):236–42. [PubMed: 16868537]
5.
Broekema M., van Eerd J.J., Oyen W.J., Corstens F.H., Liskamp R.M., Boerman O.C., Harris T.D. Synthesis of leukotriene B4 antagonists labeled with In-111 or Tc-99m to image infectious and inflammatory foci. J Med Chem. 2005;48(20):6442–53. [PubMed: 16190770]
6.
van Eerd J.E., Oyen W.J., Harris T.D., Rennen H.J., Edwards D.S., Corstens F.H., Boerman O.C. Scintigraphic imaging of infectious foci with an 111In-LTB4 antagonist is based on in vivo labeling of granulocytes. J Nucl Med. 2005;46(5):786–93. [PubMed: 15872352]
7.
van Eerd J.E., Rennen H.J., Oyen W.J., Harris T.D., Edwards D.S., Corstens F.H., Boerman O.C. Scintigraphic detection of pulmonary aspergillosis in rabbits with a radiolabeled leukotriene b4 antagonist. J Nucl Med. 2004;45(10):1747–53. [PubMed: 15471844]
8.
Barrett, J.A., E.H. Cheesman, T.D. Harris, and M. Rajopadhye, Radiopharmaceuticals for imaging infection and inflammation., in PCT Int Appl WO 9815294. 1998, Bristol Meyer Squibb.
9.
Harris, T.D., J.A. Barrett, A.P. Carpenter, and M. Rajopadhye, Vitronectin receptorantagonist pharmaceuticals., in US patent 6511649 2003, Bristol Meyer Squibb.
10.
Hubbuch A., Danho W., Zahn H. Synthesis of N-protected cysteic acid derivatives and their activated derivatives. Liebigs Ann Chem. 1979:776–783.
11.
van Eerd J.E., Laverman P., Oyen W.J., Harris T.D., Edwards D.S., Ellars C.E., Corstens F.H., Boerman O.C. Imaging of experimental colitis with a radiolabeled leukotriene B4 antagonist. J Nucl Med. 2004;45(1):89–93. [PubMed: 14734679]

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