title: Quantitative kinetics of [124I]FIAU in cat and man.
abstract: 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-1beta-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 [(124)I]FIAU was synthesized by reacting the precursor 2'-fluoro-2'-deoxy-1beta-D-arabinofuranosyluracil (FAU) with carrier-free [(124)I]NaI. The course of biodistribution of [(124)I]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 O(2) in cats only; cerebral metabolic rate of glucose and [(11)C]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 [(124)I]FIAU synthesis was 54.6% +/- 6.8%. The chemical and radiochemical purities of [(124)I]FIAU were found to be >98% and >95%, respectively. In cats, the kinetic analysis of [(124)I]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 [(124)I]FIAU uptake occurred throughout the measurement (<0.02 %ID/g; SUV, <0.4). In the patient, [(124)I]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 [(124)I]FIAU-derived radioactivity (5-10 min after injection; 0.001 %ID/g; SUV, 0.8), which cleared slowly over the 68-h imaging period.
  
  
  CONCLUSIONS
  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 [(124)I]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.
authors.affiliation: Max-Planck-Institute for Neurological Research, Center for Molecular Medicine, and Department of Neurology, University of Cologne, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Jacobs
authors.forename: I
authors.initials: I
authors.lastname: Bräunlich
authors.forename: R
authors.initials: R
authors.lastname: Graf
authors.forename: M
authors.initials: M
authors.lastname: Lercher
authors.forename: T
authors.initials: T
authors.lastname: Sakaki
authors.forename: J
authors.initials: J
authors.lastname: Voges
authors.forename: V
authors.initials: V
authors.lastname: Hesselmann
authors.forename: W
authors.initials: W
authors.lastname: Brandau
authors.forename: K
authors.initials: K
authors.lastname: Wienhard
authors.forename: W D
authors.initials: WD
authors.lastname: Heiss
mesh_terms: D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D001921:Brain / Q000000981:diagnostic imaging*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000628:therapy; D002415:Cats; D015870:Gene Expression; D015316:Genetic Therapy; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000628:therapy; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D013937:Thymidine Kinase / Q000235:genetics; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014161:Transduction, Genetic
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D001086:Arabinofuranosyluracil; C043457:fialuridine; D013937:Thymidine Kinase