N(3)-Substituted thymidine analogues V: synthesis and preliminary PET imaging of N(3)-[(18)F]fluoroethyl thymidine and N(3)-[(18)F]fluoropropyl thymidine

• Published in: Nuclear medicine and biology Vol. 35; no. 6; pp. 697 - 705
• Main Authors: Mukhopadhyay, Uday, Soghomonyan, Suren, Yeh, Hsin Hsien, Flores, Leo G, Shavrin, Aleksandr, Volgin, Andrei Y, Gelovani, Juri G, Alauddin, Mian M
• Format: Journal Article
• Language: English
• Published: United States 01.08.2008
• Subjects: Animals; Carcinoma, Non-Small-Cell Lung - diagnostic imaging; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Humans; Metabolic Clearance Rate; Mice; Mice, Nude; Organ Specificity; Pilot Projects; Positron-Emission Tomography - methods; Radiopharmaceuticals - pharmacokinetics; Thymidine - analogs & derivatives; Thymidine - pharmacokinetics; Tissue Distribution; Tyrosine - analogs & derivatives; Tyrosine - pharmacokinetics
• ISSN: 0969-8051
• DOI: 10.1016/j.nucmedbio.2008.03.007

[(18)F]-Labeled analogues of thymidine have demonstrated efficacy for PET imaging of cellular proliferation. We have synthesized two [(18)F]-labeled N(3)-substituted thymidine analogues, N(3)-[(18)F]fluoroethyl thymidine (N(3)-[(18)F]-FET) and N(3)-[(18)F]fluoropropyl thymidine (N(3)-[(18)F]-FPrT), and performed preliminary PET imaging studies in tumor-bearing mice. Thymidine was converted to its 3',5'-O-bis-tetrahydropyranyl ether, which was then converted to the N(3)-ethyl and propyl-substituted mesylate precursors. Reactions of these mesylate precursors with n-Bu(4)N[(18)F] or K[(18)F]/kryptofix followed by acid hydrolysis and HPLC purification yielded N(3)-[(18)F]-FET and N(3)-[(18)F]-FPrT, respectively. Subcutaneous (sc) xenografts of H441 human non-small cell lung cancer were established in two groups of mice (each n=6). Micro-PET images of the tumor-bearing animals were acquired after intravenous injection of N(3)-[(18)F]-FET or N(3)-[(18)F]-FPrT (3700 KBq/animal). The radiochemical yields were 2-12% (d.c.) for N(3)-[(18)F]-FET and 30-38% (d.c.) for N(3)-[(18)F]-FPrT. Radiochemical purity was >99% and calculated specific activity was >74 GBq/mumol at the end of synthesis. The accumulation of N(3)-[(18)F]-FET and N(3)-[(18)F]-FPrT in the tumor tissue at 2 h postinjection was 1.81+/-0.78 and 2.95+/-1.14 percent injected dose per gram (%ID/g), respectively; tumor/muscle ratios were 5.57+/-0.82 and 7.69+/-2.18, respectively; the unidirectional influx rates (K(i)) were 0.013 and 0.018 ml/g per minute, respectively. Two novel [(18)F]- N(3)-substituted thymidine analogues have been synthesized in good yields, high purity and high specific activity. Preliminary in vivo studies demonstrated the efficacy of these [(18)F]- N(3)-substituted thymidine analogues for PET imaging of tumors.