title: Feasibility and dosimetry studies for 18F-NOS as a potential PET radiopharmaceutical for inducible nitric oxide synthase in humans.
abstract: Nitric oxide (NO), the end product of the inducible form of NO synthase (iNOS), is an important mediator of a variety of inflammatory diseases. Therefore, a radiolabeled iNOS radiopharmaceutical for assessing iNOS protein concentration as a marker for its activity would be of value to the study and treatment of NO-related diseases. We recently synthesized an (18)F-radiolabeled analog of the reversible NOS inhibitor, 2-amino-4-methylpyridine ((18)F-NOS), and confirmed its utility in a murine model of lung inflammation. To determine its potential for use in humans, we measured (18)F-NOS myocardial activity in patients after orthotopic heart transplantation (OHT) and correlated it with pathologic allograft rejection, tissue iNOS levels, and calculated human radiation dosimetry.
  
  
  METHODS
  Two groups were studied-a kinetic analysis group and a dosimetry group. In the kinetic analysis group, 10 OHT patients underwent dynamic myocardial (18)F-NOS PET/CT, followed by endomyocardial biopsy. Myocardial (18)F-NOS PET was assessed using volume of distribution; standardized uptake values at 10 min; area under the myocardial moment curve (AUMC); and mean resident time at 5, 10, and 30 min after tracer injection. Tissue iNOS levels were measured by immunohistochemistry. In the dosimetry group, the biodistribution and radiation dosimetry were calculated using whole-body PET/CT in 4 healthy volunteers and 12 OHT patients. The combined time-activity curves were used for residence time calculation, and organ doses were calculated with OLINDA.
  
  
  RESULTS
  Both AUMC at 10 min (P < 0.05) and tissue iNOS (P < 0.0001) were higher in patients exhibiting rejection than in those without rejection. Moreover, the (18)F-NOS AUMC at 10 min correlated positively with tissue iNOS at 10 min (R(2) = 0.42, P < 0.05). (18)F-NOS activity was cleared by the hepatobiliary system. The critical organ was the bladder wall, with a dose of 95.3 μGy/MBq, and an effective dose of 15.9 μSv/MBq was calculated.
  
  
  CONCLUSIONS
  Myocardial (18)F-NOS activity is increased in organ rejection (a condition associated with increased iNOS levels) and correlates with tissue iNOS measurements with acceptable radiation exposure. Although further modifications to improve the performance of (18)F-NOS are needed, these data show the feasibility of PET of iNOS in the heart and other tissues.
authors.affiliation: Division of Radiological Sciences, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: Herrero
authors.forename: Richard
authors.initials: R
authors.lastname: Laforest
authors.forename: Kooresh
authors.initials: K
authors.lastname: Shoghi
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.forename: Gregory
authors.initials: G
authors.lastname: Ewald
authors.forename: John
authors.initials: J
authors.lastname: Pfeifer
authors.forename: Eric
authors.initials: E
authors.lastname: Duncavage
authors.forename: Kitty
authors.initials: K
authors.lastname: Krupp
authors.forename: Robert
authors.initials: R
authors.lastname: Mach
authors.forename: Robert
authors.initials: R
authors.lastname: Gropler
mesh_terms: D000328:Adult; D005240:Feasibility Studies; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000032:analysis*; D049268:Positron-Emission Tomography / Q000379:methods*; D011829:Radiation Dosage; D011874:Radiometry; D019275:Radiopharmaceuticals; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D052247:Nitric Oxide Synthase Type II