title: Human pharmacokinetic and dosimetry studies of [(18)F]FHBG: a reporter probe for imaging herpes simplex virus type-1 thymidine kinase reporter gene expression.
abstract: 9-[4-[(18)F]fluoro-3-(hydroxymethyl)butyl]guanine ([(18)F]FHBG) has been used as a reporter probe to image expression of herpes simplex virus type-1 thymidine kinase (HSV1-tk) reporter gene in living animals. Our aim was to study the kinetics, biodistribution, stability, dosimetry, and safety of [(18)F]FHBG in healthy human volunteers, preparatory to imaging patients undergoing HSV1-tk gene therapy.
  
  
  METHODS
  [(18)F]FHBG was synthesized with a specific activity of 37,000--444,000 GBq/mmol and a radiochemical purity > 99%. Ten healthy volunteers consented to participate in the study. A transmission scan was obtained before bolus injection of 70.3--229.4 MBq [(18)F]FHBG into a hand vein, followed by dynamic PET imaging with 4 consecutive emission scans. Warmed hand-vein blood was withdrawn at various times after injection for blood time--activity measurements. Electrocardiography, blood pressure, and blood and urine pharmacologic parameters were measured before and after injection of the [(18)F]FHBG tracer (n = 5). The stability of [(18)F]FHBG in the urine was analyzed. Attenuation-corrected images were reconstructed using the ordered-subsets expectation maximization algorithm. Image region-of-interest time-activity data were used with the MIRD program to estimate absorbed radiation dosages.
  
  
  RESULTS
  [(18)F]FHBG had rapid blood clearance; only 8.42% +/- 4.76% (mean +/- SD) of the peak blood activity remained at approximately 30 min. The average ratio of plasma activity to whole-blood activity during the study was 0.91 +/- 0.04. Penetration of [(18)F]FHBG across the blood-brain barrier was not observed. The primary routes of clearance were renal and hepatobiliary. High activities were observed in the bladder, gut, liver, and kidneys, but <0.0002% of the injected dose per gram was observed in other tissues. In the urine, 83% of activity 180 min after injection was stable [(18)F]FHBG. Blood and urine pharmacologic parameters did not change significantly after injection of the [(18)F]FHBG tracer. The bladder absorbed the highest radiation dose.
  
  
  CONCLUSIONS
  [(18)F]FHBG has the desirable in vivo characteristics of stability, rapid blood clearance, low background signal, biosafety, and acceptable radiation dosimetry in humans. This study forms the foundation for using [(18)F]FHBG in applications to monitor HSV1-tk reporter gene expression.
authors.affiliation: Crump Institute for Molecular Imaging, UCLA--DOE Laboratory of Structural Biology and Molecular Medicine, UCLA School of Medicine, University of California, Los Angeles, 90095-1770, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yaghoubi
authors.forename: J R
authors.initials: JR
authors.lastname: Barrio
authors.forename: M
authors.initials: M
authors.lastname: Dahlbom
authors.forename: M
authors.initials: M
authors.lastname: Iyer
authors.forename: M
authors.initials: M
authors.lastname: Namavari
authors.forename: N
authors.initials: N
authors.lastname: Satyamurthy
authors.forename: R
authors.initials: R
authors.lastname: Goldman
authors.forename: H R
authors.initials: HR
authors.lastname: Herschman
authors.forename: M E
authors.initials: ME
authors.lastname: Phelps
authors.forename: S S
authors.initials: SS
authors.lastname: Gambhir
mesh_terms: D000328:Adult; D002138:Calibration; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D017930:Genes, Reporter; D006147:Guanine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000493:pharmacokinetics; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: C113308:9-(4-fluoro-3-hydroxymethylbutyl)guanine; D019275:Radiopharmaceuticals; D006147:Guanine; D013937:Thymidine Kinase