Synthesis and metabolism of radiolabeled folate -chelate conjugates
Abstract
The development of radiolabeled folate-chelate conjugates could result in clinically useful diagnostic imaging agents for several types of cancers that over-express folate receptors. In particular, 111In-DTPA-folate has shown considerable utility as a diagnostic indicator of folate-receptor-positive, KB cell tumor xenografts in athymic mouse models. After i.v. administration to this mouse model, most of the radiotracer is excreted into the urine. The radiolabel retained by the mouse model is present almost exclusively in the KB cell tumor xenografts and proximal convoluted tubules of the kidneys, which are sites of increased folate receptor density. The present research was undertaken to: (1) examine the chemical form of the radiolabel retained in athymic mouse KB cell tumor xenografts and kidney after i.v. administration of 111In-DTPAfolate; (2) synthesize a Tc-99m-based DTPA-folate radiotracer using low doses of the DTPA-folate conjugate; (3) explore the possibility of using neutral endopeptidase-24.11 to cleave a peptide linker connecting the “111In-DTPA” and “folate-receptor-targeting” moieties of the 111In-DTPA-folate molecule to modify the chemical form of the radiolabel for increased renal clearance. The results of this research indicate: (1) the 111In-DTPA-folate radiotracer is largely present as the intact radiotracer in KB cell tumor and kidney for up to four hours after i.v administration to athymic mouse models; (2) low levels of the DTPA-folate conjugate can be labeled with the “Tc(CO)3+” moiety via the [ 99mTc(CO)3(H2O)3]+ intermediate to produce the [99mTc]Tc(CO)3DTPA-folate radiotracer, which selectively accumulates in folate receptor positive tumor and kidney tissues; (3) neutral endopeptidase-24.11 degrades 111In-DTPA-Gin-Gin-Phe-Phe-Gly-Leu-Met-Lys(N-ϵ-pteroyl)-OH into two radioactive products in vitro, one of which appears to be 111InDTPA.
Degree
Ph.D.
Advisors
Green, Purdue University.
Subject Area
Pharmacology|Nuclear chemistry|Oncology
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