Quantitative Kinetics of [124I]FIAU in Cat and Man

Journal of Nuclear Medicine

Wolf-Dieter Heiss¹  Volker Hesselmann¹  Andreas Jacobs¹  Klaus Wienhard¹  Wolfgang Brandau¹  Takayuki Sakaki¹  Ines Bräunlich¹  Jürgen Voges¹  Martin Lercher¹  Rudolf Graf¹ 

[1] Max-Planck-Institute for Neurological Research, Center for Molecular Medicine, and Departments of Neurology, Stereotactic Neurosurgery, and Radiology, University of Cologne, Cologne; and Department of Nuclear Chemistry and Radiopharmacy, University of Essen, Essen, Germany Max-Planck-Institute for Neurological Research, Center for Molecular Medicine, and Departments of Neurology, Stereotactic Neurosurgery, and Radiology, University of Cologne, Cologne; and Department of Nuclear Chemistry and Radiopharmacy, University of Essen, Essen, Germany Max-Planck-Institute for Neurological Research, Center for Molecular Medicine, and Departments of Neurology, Stereotactic Neurosurgery, and Radiology, University of Cologne, Cologne; and Department of Nuclear Chemistry and Radiopharmacy, University of Essen, Essen, Germany

关键词: 2′-fluoro-2′-deoxy-1β-d-arabinofuranosyl-5-iodouracil;    tracer kinetics;    PET;    molecular imaging;    gene therapy;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

For the assessment of the efficacy of clinical gene therapy trials, different imaging modalities have been developed that enable a noninvasive assessment of location, magnitude, and duration of transduced gene expression in vivo. These imaging methods rely on a combination of an appropriate marker gene and a radiolabeled or paramagnetic marker substrate that can be detected by PET or MRI. Here, we assess whether the nucleoside analog 2′-fluoro-2′-deoxy-1β-d-arabinofuranosyl-5-iodouracil (FIAU), a specific marker substrate for herpes simplex virus type 1 thymidine kinase (HSV-1-tk) gene expression, penetrates the blood–brain barrier (BBB) as an essential prerequisite for a noninvasive assessment of HSV-1-tk gene expression in gliomas. Methods: No-carrier-added [124I]FIAU was synthesized by reacting the precursor 2′-fluoro-2′-deoxy-1β-d-arabinofuranosyluracil (FAU) with carrier-free [124I]NaI. The course of biodistribution of [124I]FIAU was investigated in anesthetized cats (n = 3; organs) and in one patient with a recurrent glioblastoma (plasma and brain) by PET imaging over several hours (cats, 1–22 h) to several days (patient, 1–68 h). FIAU PET was performed in conjunction with multitracer PET imaging (cerebral blood flow and cerebral metabolic rate of O2 in cats only; cerebral metabolic rate of glucose and [11C]methionine in all subjects). A region-of-interest analysis was performed on the basis of coregistered high-resolution MR images. The average radioactivity concentration was determined, decay corrected, and recalculated as percentage injected dose per gram of tissue (%ID/g) or as standardized uptake values (SUVs). Results: The average chemical yield of [124I]FIAU synthesis was 54.6% ± 6.8%. The chemical and radiochemical purities of [124I]FIAU were found to be >98% and >95%, respectively. In cats, the kinetic analysis of [124I]FIAU-derived radioactivity showed an early peak (1–2 min after injection) in heart and kidneys (0.20 %ID/g; SUV, 4.0) followed by a second peak (10–20 min after injection) in liver and spleen (0.16 %ID/g; SUV, 3.2) with subsequent clearance from tissues and a late peak in the bladder (10–15 h after injection). In the unlesioned cat brain, no substantial [124I]FIAU uptake occurred throughout the measurement (<0.02 %ID/g; SUV, <0.4). In the patient, [124I]FIAU uptake in normal brain was also very low (<0.0002 %ID/g; SUV, <0.16). In contrast, the recurrent glioblastoma revealed relatively high levels of [124I]FIAU-derived radioactivity (5–10 min after injection; 0.001 %ID/g; SUV, 0.8), which cleared slowly over the 68-h imaging period. Conclusion: The PET marker substrate FIAU does not penetrate the intact BBB significantly and, hence, is not the marker substrate of choice for the noninvasive localization of HSV-1-tk gene expression in the central nervous system under conditions in which the BBB is likely to be intact. However, substantial levels of [124I]FIAU-derived radioactivity may occur within areas of BBB disruption (e.g., glioblastoma), which is an essential prerequisite for imaging clinically relevant levels of HSV-1-tk gene expression in brain tumors after gene therapy by FIAU PET. For this purpose, washout of nonspecific radioactivity should be allowed for several days.

【 授权许可】

Unknown