Peptide Based Radiopharmaceuticals: Specific Construct Approach
The objective of this project was to develop receptor based peptides for diagnostic imaging and therapy. A series of peptides related to cell adhesion molecules (CAM) and immune regulation were designed for radiolabeling with 99mTc and evaluated in animal models as potential diagnostic imaging agents for various disease conditions such as thrombus (clot), acute kidney failure, and inflection/inflammation imaging. The peptides for this project were designed by the industrial partner, Palatin Technologies, (formerly Rhomed, Inc.) using various peptide design approaches including a newly developed rational computer assisted drug design (CADD) approach termed MIDAS (Metal ion Induced Distinctive Array of Structures). In this approach, the biological function domain and the 99mTc complexing domain are fused together so that structurally these domains are indistinguishable. This approach allows construction of conformationally rigid metallo-peptide molecules (similar to cyclic peptides) that are metabolically stable in-vivo. All the newly designed peptides were screened in various in vitro receptor binding and functional assays to identify a lead compound. The lead compounds were formulated in a one-step 99mTc labeling kit form which were studied by BNL for detailed in-vivo imaging using various animals models of human disease. Two main peptides usingMIDAS approach evolved and were investigated: RGD peptide for acute renal failure and an immunomodulatory peptide derived from tuftsin (RMT-1) for infection/inflammation imaging. Various RGD based metallopeptides were designed, synthesized and assayed for their efficacy in inhibiting ADP-induced human platelet aggregation. Most of these peptides displayed biological activity in the 1-100 µM range. Based on previous work by others, RGD-I and RGD-II were evaluated in animal models of acute renal failure. These earlier studies showed that after acute ischemic injury the renal cortex displays RGD receptor with higher density. The results have indicated good diagnostic potential for their use in this clinical situation, as an imaging agent to diagnose ischemic renal injury and differentiate from other causes. Very promising results were obtained with newly developed tuftsin related metallopeptides. A number of these peptides displayed high potency (nM range) in imaging infection. Antagonists were successfully used to image experimentally induced abscesses in rodents. One of the antagonists, termed 99mTc-RMT-1, was evaluated in rabbits and dogs for its applicability as infection/inflammation imaging agent. Both in dog and rabbit infection/inflammation models 99mTc-RMT-1 could be used for rapid scintigraphic diagnosis. A very high and rapid uptake was observed in both soft tissue and bone infection providing a good target to background contrast. The agent also allowed distinction between bone fracture and osteomyelitis. All these results warrant human clinical trials with 99mTc-RMT-1 which may help replace hazardous ex-vivo WBC labeling procedures that are current clincial modality for imaging infection foci.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC)
- DOE Contract Number:
- AC02-76CH00016
- OSTI ID:
- 770462
- Report Number(s):
- DOE/CH/00016-T47; BNL-83306-1997; CRADA # C/BNL--94-07
- Country of Publication:
- United States
- Language:
- English
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