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 5 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 mGy/MBq, and an effective dose of 15.9 mSv/MBq was calculated. Conclusion: 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.

PET of Poly (ADP-Ribose) Polymerase Activity in Cancer: Preclinical Assessment and First In-Human Studies

“…Organ residence times and estimates of best-and worse-case scenarios were calculated from the percentage injected dose per organ derived from the human images and entered into the OLINDA/ EXM software program (version 1.1; Vanderbilt University, Nashville, Tenn) to estimate individual organ doses and whole-body effective doses (24). Given the small number of subjects for the human dosimetry study, statistical analysis was not performed on the human image data.…”

Imaging Pulmonary Inducible Nitric Oxide Synthase Expression with PET

“…This tracer may also still provide useful information about iNOS expression in clinical trials in which a baseline scan can be obtained before an antiinflammatory therapy is initiated. Nevertheless, 1 previously published study investigating 18 F-NOS in transplanted heart grafts demonstrated a small increase in signal, suggesting that further chemical modifications may be needed to improve in vivo binding (23). Such tracers could potentially image a wider range of in vivo iNOS expression in the lungs as well as other organ systems.…”

“…Spirometry testing was repeated after endotoxin administration. 18 F-NOS was synthesized as previously described (23). Vital sign monitoring was performed throughout the study as previously reported (24).…”

“…Thus, noninvasive methods for imaging iNOS expression may be useful as a more specific biomarker of inflammatory lung disease activity. We have developed a PET tracer, 18 F-NOS, that binds to iNOS (22) and has been used to image iNOS expression in heart transplant recipients (23). To assess its potential utility for imaging lung-related inflammation, we hypothesized that 18 F-NOS could image iNOS expression in human lungs after endotoxin instillation.…”

Natural polyphenolic complex of grape wine shows protective effect on radioinduced nitrative stress in rat aorta

“…NO є важливим і унікальним медіатором багатьох фізіологічних функцій та патологічних процесів. NO генерується у разі окиснення L-аргініну до L-цитруліну ензимами родини синтаз оксиду азоту (NO-синтаза, NOS; L-аргінін, NADPH: кисень оксидоредуктаза; [EC 1.14.13.39]) [14]. За фізіологічних умов пул NO у судинах забезпечується функціонуванням ендотеліальної ізоформи NOS (eNOS).…”