99mTc-HYNIC-folate: a novel receptor-based targeted radiopharmaceutical for tumor imaging.
The folate receptor is overexpressed in a wide variety of human tumors. Conjugates of folate have been shown to be selectively taken up by tumor cells via the folate receptor. In this study, a novel radiopharmaceutical, 99mTc-6-hydrazinonicotinamido-hydrazido (HYNIC)-folate, was synthesized and evaluated for its efficacy as a targeted agent for the imaging of tumors that overexpress the folate receptor.


METHODS
HYNIC-folate was synthesized and radiolabeled with 99mTc using tricine and trisodium triphenylphosphine-3,3',3"-trisulfonate as coligands. The receptor binding properties of 99mTc-HYNIC-folate were studied in cultured tumor cells that overexpress the folate receptor. The tumor-localizing properties of 99mTc-HYNIC-folate were then evaluated in C57BL/6 mice bearing subcutaneously implanted folate receptor-positive syngeneic tumors. Tissue distribution was determined at two different time points, and gamma camera images were collected on two animals.


RESULTS
The folate receptor-mediated uptake of 99mTc-HYNIC-folate by cultured tumor cells was approximately 300 times higher than the nonspecific binding determined in the presence of 1 mmol/L free folic acid. Excellent tumor selectivity was also shown in the animal model; tumor-to-blood ratios reached 55+/-19 and 81+/-6 at 4 and 24 h after injection, respectively. Tumor uptake of the radiotracer was blocked by the co-injection of 100 microg free folate. Tumors were clearly identifiable on the gamma camera images, with the kidneys and the bladder as the only normal organs showing high levels of the radiotracer.


CONCLUSIONS
99mTc-HYNIC-folate is a promising, novel receptor-specific radiopharmaceutical with potential applications in the imaging of human tumors.
Guo
W
W
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, Ohio State University, Columbus 43210, USA.
Hinkle
G H
GH
Lee
R J
RJ
D000818:Animals; D002277:Carcinoma / Q000000981:diagnostic imaging / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis*; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D007624:KB Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D011956:Receptors, Cell Surface / Q000032:analysis*; D012513:Sarcoma, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000378:metabolism
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D015609:Organotechnetium Compounds; D011956:Receptors, Cell Surface; C121444:technetium Tc 99m-hynic-folate; D005492:Folic Acid