Synthesis and preclinical evaluation of a new C-6 alkylated pyrimidine derivative as a PET imaging agent for HSV1-tk gene expression

American Journal of Nuclear Medicine and Molecular Imaging

Stefanie D Krämer¹  Mariana Born¹  Evelyn Trauffer¹  Roger Slavik¹  Ursina Müller¹  Adrienne Müller¹  Charlene Ranadheera¹  Tobias L Ross¹  Leonardo Scapozza¹  Simon M Ametamey¹  Selena Milicevic Sephton¹ 

关键词: HSV1-TK;    reporter gene;    gene expression monitoring;    PET;    [18F]FHOMP;    [18F]FHBG;   

DOI  :  

学科分类：过敏症与临床免疫学

来源: e-Century Publishing Corporation

【 摘 要 】

[¹⁸F]FHOMP (6-((1-[¹⁸F]-fluoro-3-hydroxypropan-2-yloxy)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione), a C-6 substituted pyrimidine derivative, has been synthesized and evaluated as a potential PET agent for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression. [¹⁸F]FHOMP was prepared by the reaction of the tosylated precursor with tetrabutylammonium [¹⁸F]-fluoride followed by acidic cleavage of the protecting groups. In vitro cell accumulation of [¹⁸F]FHOMP and [¹⁸F]FHBG (reference) was studied with HSV1-tk transfected HEK293 (HEK293TK+) cells. Small animal PET and biodistribution studies were performed with HEK293TK+ xenograft-bearing nude mice. The role of equilibrative nucleoside transporter 1 (ENT1) in the transport and uptake of [¹⁸F] FHOMP was also examined in nude mice after treatment with ENT1 inhibitor nitrobenzylmercaptopurine ribonucleoside phosphate (NBMPR-P). [¹⁸F]FHOMP was obtained in a radiochemical yield of ~25% (decay corrected) and the radiochemical purity was greater than 95%. The uptake of [¹⁸F]FHOMP in HSV1-TK containing HEK293TK+ cells was 52 times (at 30 min) and 244 times (at 180 min) higher than in control HEK293 cells. The uptake ratios between HEK293TK+ and HEK293 control cells for [¹⁸F]FHBG were significantly lower i.e. 5 (at 30 min) and 81 (240 min). In vivo, [¹⁸F]FHOMP accumulated to a similar extend in HEK293TK+ xenografts as [¹⁸F]FHBG but with a higher general background. Blocking of ENT1 reduced [¹⁸F]FHOMP uptake into brain from a standardized uptake value (SUV) of 0.10±0.01 to 0.06±0.02, but did not reduce the general background signal in PET. Although [¹⁸F]FHOMP does not outperform [¹⁸F]FHBG in its in vivo performance, this novel C-6 pyrimidine derivative may be a useful probe for monitoring HSV1-tk gene expression in vivo.

【 授权许可】

Unknown