Preparation of Low Valent Tc(1) Imaging Agents

University Of Missouri-Columbia, Columbia MO

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Abstract

DESCRIPTION (provided by applicant): The research project outlined in this proposal holds the potential for development of one or more radiolabeled, site-specific, Gastrin Releasing Peptide (GRP), diagnostic/therapeutic radiopharmaceuticals. Briefly, the proposal describes the design and development of new conjugates of the form [Dpr-(Y)-BBN(7-14)NH2], where Dpr = diaminopropionic acid, BBN = Bombesin, and Y = a series of hydrophilic amino acid tethers including the residues glutamic acid, aspartic acid, glutamine, and asparagine. These conjugates, when radiolabeled with the new low valent Tc-99m synthon [99mTc(H2O)3(CO)3]+, hold potential to produce high specific activity products that specifically target human cancers overexpressing the GRP receptor (GRPr). The specific objectives of this proposal are: 1) Synthesize a limited number of GRPr-positive ligands of the form [Dpr-(Y)-BBN(7-14)NH2] via solid phase peptide synthetic techniques; 2) Metallate the newly constructed ligands with Iow-valent Tc(I)(CO)3 and Re(I)(CO)3 cores; 3) Evaluate the binding affinity of the metallated [Dpr-(Y)-BBN(7-14)NH2]-conjugates in vitro, using GRPr-positive, human prostate, cancer cell lines (PC-3); 4) Evaluate the in vivo pharmacokinetics of those 99mTc(I)-labeled analogs demonstrating high receptor binding affinities (i.e., Kd=5nM) in normal (CF-1) mouse models; 5) Optimize and validate the "matched pair" 188Re-conjugate of the most promising [Dpr-(Y)-BBN(7-14)NH2]-derivative via the newly developed radiosynthon [l88Re(H2O)3(CO)3]+. All of the metallated conjugates, will be synthesized, purified, and characterized at both tracer (99mTc and 188Re) and macroscopic (99Tc and 186Re) levels. In vitro and in vivo screening of each of the new metallated conjugates will serve to evaluate the properties of receptormediated internalization and cancer cell uptake. Identification of even a single diagnostic analog provides impetus for future evaluation of this new class of radiopharmaceuticals, via FDA approved clinical trials, in human patients.