Spacer length effects on in vitro imaging and surface accessibility of fluorescent inhibitors of prostate specific membrane antigen.
Prostate-specific membrane antigen (PSMA), a type II transmembrane protein, has been becoming an active target for imaging and therapeutic applications for prostate cancer. Recently, the development of its various chemical inhibitor scaffolds has been explored to serve as carriers for therapeutic or diagnostic payloads targeted to PSMA-positive tumor cells. However, there have been few efforts to definitively determine the optimal length of linker between PSMA inhibitor cores and their payload molecules with regard to the affinity to PSMA and in vitro performance. In our present model study, three spacer-length varied fluorescent inhibitors (FAM-CTT-54, FAM-X-CTT-54 and FAM-PEG(8)-CTT-54) were synthesized, and further enzymatic inhibition studies displayed linker length-dependent changes in: inhibitory potency (IC(50)=0.41 nM, 0.35 nM, 1.93 nM), modes of binding (reversible, slowly reversible, irreversible), respectively. Furthermore, cell-labeling imaging revealed the spacer length-related change of fluorescence intensity (FAM-X-CTT-54>FAM-PEG(8)-CTT-54>FAM-CTT-54). These results suggest that selection of linkers and their lengths will be important considerations in the development of next-generation prostate tumor-targeted imaging probes and therapeutic agents that specifically home to PSMA on tumor cells.
Department of Chemistry, Washington State University, Pullman, WA 99164-4630, United States.
Tiancheng
T
Liu
Jessie R
JR
Nedrow-Byers
Mark R
MR
Hopkins
Clifford E
CE
Berkman
D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005452:Fluoresceins / Q000138:chemical synthesis / Q000737:chemistry*; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000188:drug therapy
C554453:FAMX-CTT-54; D005452:Fluoresceins; D005456:Fluorescent Dyes; D009943:Organophosphorus Compounds; D017430:Prostate-Specific Antigen