TY - JOUR
T1 - Feasibility and dosimetry studies for 18F-NOS as a potential PET radiopharmaceutical for inducible nitric oxide synthase in humans
AU - Herrero, Pilar
AU - Laforest, Richard
AU - Shoghi, Kooresh
AU - Zhou, Dong
AU - Ewald, Gregory
AU - Pfeifer, John
AU - Duncavage, Eric
AU - Krupp, Kitty
AU - Mach, Robert
AU - Gropler, Robert J.
PY - 2012/6
Y1 - 2012/6
N2 - 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 18F-radiolabeled analog of the reversible NOS inhibitor, 2-amino-4-methylpyridine ( 18F-NOS), and confirmed its utility in a murine model of lung inflammation. To determine its potential for use in humans, we measured 18F-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 18F-NOS PET/CT, followed by endomyocardial biopsy. Myocardial 18F-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 18F-NOS AUMC at 10 min correlated positively with tissue iNOS at 10 min (R 2 = 0.42, P < 0.05). 18F-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. Conclusion: Myocardial 18F-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 18F-NOS are needed, these data show the feasibility of PET of iNOS in the heart and other tissues.
AB - 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 18F-radiolabeled analog of the reversible NOS inhibitor, 2-amino-4-methylpyridine ( 18F-NOS), and confirmed its utility in a murine model of lung inflammation. To determine its potential for use in humans, we measured 18F-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 18F-NOS PET/CT, followed by endomyocardial biopsy. Myocardial 18F-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 18F-NOS AUMC at 10 min correlated positively with tissue iNOS at 10 min (R 2 = 0.42, P < 0.05). 18F-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. Conclusion: Myocardial 18F-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 18F-NOS are needed, these data show the feasibility of PET of iNOS in the heart and other tissues.
KW - Cardiac
KW - Molecular imaging
KW - Positron emission tomography
UR - http://www.scopus.com/inward/record.url?scp=84861914393&partnerID=8YFLogxK
U2 - 10.2967/jnumed.111.088518
DO - 10.2967/jnumed.111.088518
M3 - Article
C2 - 22582045
AN - SCOPUS:84861914393
SN - 0161-5505
VL - 53
SP - 994
EP - 1001
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 6
ER -