Synthesis and preliminary biological evaluation of a 99mTc-labeled thymidine analog as a potential candidate for tumor imaging

Objectives To develop a novel technetium-99m-labeled thymidine analog, [99mTc]- N-{N’-[2-sulfanyl-ethylamino)acetyl]-2-aminoethylsulfanyl-1-hexanamide}- thymidine (99mTc-NHT), by using thymidine coupled with N2S2 ligand forming a stable complex as a potential SPECT imaging agent.

Methods The labeling precursor N-{N’-[2-sulfanylethylamino)acetyl]-2-aminoethyl sulfanyl-1-hexanamide}-thymidine (NHT) was synthesized in a five-step reaction sequence. Using SnCl2 as reducing agent, and in the presence of sodium glucoheptonate, a series of studies were performed to optimize labeling efficiency of 99mTc-NHT. The radiolabeling yield (RLY) and radiochemical purity (RCP) of 99mTc-NHT were determined by thin-layer chromatography (TLC). The in vitro stability of 99mTc-NHT was determined every 1h at room temperature. The partition coefficients of 99mTc-NHT were determined in n-octanol and phosphate buffer (PB) (pH 7.0 and pH 7.4, respectively) and the biodistribution of 99mTc-NHT was performed in tumor-bearing mice.

Results The chemical structures of the labeling precursor and its intermediates were verified by IR, 1HNMR and MS. 99mTc-NHT was stable up to 6 h in aqueous solution and radiochemical purity was over 95% at selected condition. Partition coefficients (lgP)were 0.76 and 0.56 at pH 7.0 and pH 7.4 of the phosphate buffer, respectively. Biodistribution of 99mTc-NHT in mice showed that the high initial uptake of 99mTc-NHT in vivo and the clearance was rapid.At 2 h p.i., the ratios of tumor-to-muscle, tumor-to-bone and tumor-to-blood were 4.41±0.32, 2.45±0.24 and 1.51±0.18, respectively.

Conclusions 99mTc-NHT is probably a potential SPECT tumor imaging agent and further study is needed.

Research Support Supported by Natural Science Foundation of Jiangsu Province (BK2008112) and Science Foundation of Health Department of Jiangsu Province (H200624)