Quantitative kinetics of [I-124]FIAU in cat and man

For the assessment of the efficacy of clinical gene therapy trials, differe nt imaging modalities have been developed that enable a noninvasive assessm ent of location, magnitude, and duration of transduced gene expression in v ivo. These imaging methods rely on a combination of an appropriate marker g ene and a radiolabeled or paramagnetic marker substrate that can be detecte d by PET or MRI. Here, we assess whether the nucleoside analog 2'-fluoro-2' -deoxy-1 beta -D-arabinoiuranosyl-5-iodouracil (FIAU), a specific marker su bstrate for herpes simplex virus type 1 thymidine kinase (HSV-I-lk) gene ex pression, penetrates the blood-brain barrier (BBB) as an essential prerequi site for a noninvasive assessment of HSV-1-tk gene expression in gliomas. M ethods: No-carrier-added [I-124]FIAU was synthesized by reacting the precur sor 2'-fluoro-2'-deoxy-1 beta -D-arabinofuranosyluracil (FAU) with carrier- free [I-124]Nal. The course of biodistribution of [I-124]FIAU was investiga ted in anesthetized cats (n = 3; organs) and in one patient with a recurren t 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 conjun ction with multitracer PET imaging (cerebral blood flow and cerebral metabo lic rate of O-2 in cats only; cerebral metabolic rate of glucose and [C-11] methionine in all subjects). A region-of-interest analysis was performed on the basis of coregistered high-resolution MR images. The average radioacti vity concentration was determined, decay corrected, and recalculated as per centage injected dose per gram of tissue (%ID/g) or as standardized uptake values (SUVs). Results: The average chemical yield of [I-124]FIAU synthesis was 54.6% +/- 6.8%. The chemical and radiochemical purities of [I-124]FIAU were found to be >98% and >95%, respectively. in cats, the kinetic analysi s of [I-124]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 [I-124] FIAU uptake occurred throughout the measurement (<0.02 %ID/g; SUV, <0.4). I n the patient, [I-124]FIAU uptake in normal brain was also very low (<0.000 2 %ID/g; SUV, <0.16), In contrast, the recurrent glioblastoma revealed rela tively high levels of [I-124]FIAU-derived radioactivity (5-10 min after inj ection; 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 in tact BBB significantly and, hence, is not the marker substrate of choice fo r the noninvasive localization of HSV-1-tk gene expression in the central n ervous system under conditions in which the BBB is likely to be intact. How ever, substantial levels of [I-124]FIAU-derived radioactivity may occur wit hin areas of BBB disruption (e.g., glioblastoma), which is an essential pre requisite for imaging clinically relevant levels of HSV-1-tk gene expressio n in brain tumors after gene therapy by FIAU PET. For this purpose, washout of nonspecific radioactivity should be allowed for several days.