Design, synthesis, and evaluation of radiolabeled bombesin conjugates for the diagnosis of breast cancer
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Gastrin-releasing peptide (GRP) receptors are overexpressed on approximately two thirds (62-71%) of primary breast carcinomas and all (100%) of the corresponding metastatic sites. These receptors may be targeted with bombesin (BBN), a tetradecapeptide initially isolated from the skin of the fire bellied toad Bombina bombina, which binds to GRP receptors with both high affinity and specificity. These facts were exploited to develop a series of [superscript 99m]Tc-(CO)[subscrip 3]-X-Y-BBN(7-14)NH2 derivatives, where X = PZ1 or DPR and Y = [Beta]Ala, GGG, GSG, Peg5, Peg8, SGS, or SSS, whose ability to detect and diagnose breast cancer was analyzed. Among these conjugates, the 99mTc-(H[subscript 2]O) (CO)[subscript 3]-DPR-Y-BBN(7-14)NH2 analogs containing the amino acid spacer sequences GSG and SSS exhibited the highest levels of receptor-mediated accumulation and retention in the GRP receptor positive tissues of T47-D tumor-bearing SCID mice. Due to both their moderate residualization in tumor tissue and their rapid clearance from nontarget tissues, these derivatives demonstrated favorable tumor-to-background ratios, which allowed for the clear visualization of tumor tissue. This tumor tissue was clearly visible despite the presence of low levels of background radioactivity.
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