Development of Flourinated NP-59: A Revival of Cholesterol Utilization Imaging with PET

Abstract

Background: Imaging of cholesterol utilization is possible with the iodine-131 scintiscanning/SPECT agent, NP-59. This agent provided a non-invasive measure of adrenal function and steroid synthesis. However, iodine isotopes resulted in poor resolution, manufacturing challenges, and high radiation dosimetry to patients that have limited their use and clinical impact. A fluorine-18 analogue would address these shortcomings while retaining the ability to image cholesterol utilization. Purpose: The goal of this study was to prepare and evaluate a fluorine-18 analogue of NP-59 to serve as a PET imaging agent for functional imaging of the adrenal glands based on cholesterol use. Previous attempts to prepare such an analogue of NP-59 have proven elusive. Preclinical and clinical evaluation could be carried out once the new fluorine analogue of NP-59 production was established. Methods: The recent development of a new reagent for fluorination along with an improved route to the NP-59 precursor allowed for the preparation of a fluorine analogue of NP-59, FNP-59. The radiochemistry for the fluorine-18 radiolabeled ¹⁸F-FNP-59 is described, rodent radiation dosimetry studies and in vivo imaging in New Zealand rabbits was carried out. After in vivo toxicity studies, an IND approval was obtained and the first in human images with dosimetry using the agent were acquired. Results: In vivo toxicity studies demonstrated that FNP-59 is safe for use at intended dose. Biodistribution studies with ¹⁸F-FNP-59 demonstrated a similar pharmacokinetic profile to NP-59, but with decreased radiation exposure. In vivo animal images demonstrate expected uptake in tissues that utilize cholesterol: gallbladder, liver, and adrenal glands. First in human images had no adverse events and demonstrated accumulation in target tissues (liver and adrenal glands). Manipulation of uptake was also demonstrated with patients that received cosyntropin, resulting in improved uptake. Conclusion: ¹⁸F-FNP-59 provided higher resolution images, with lower radiation dose to the subjects. It has the potential to provide a non-invasive test for patients with adrenocortical diseases.