Preclinical Biodistribution and Human Radiation Dosimetry Estimates of [¹⁸F]FNP-59: a Radiotracer for Imaging Cholesterol Trafficking

Objectives: The synthesis and early preclinical evaluation of [¹⁸F]FNP-59, a novel fluorinated analogue of NP-59 and cholesterol, was previously reported.[1] In this work, studies were carried out to determine the biodistribution for human radiation dosimetry estimates of [¹⁸F]FNP-59 (Figure 1). NP-59 utility was limited due its high radiation dose; our objective is to demonstrate improved dosimetry and imaging properties with its fluorine-18 analogue, [¹⁸F]FNP-59.

Methods: Biodistribution experiments were conducted at 10, 30, 60, 120, and 360 min post-injection of [¹⁸F]FNP-59. Briefly, male (n = 10) and female (n = 10) Sprague-Dawley rats (weighing 171 - 339 g) were anesthetized with isoflurane (5% induction, 1-2% maintenance), injected i.v. with [¹⁸F]FNP-59 (3349 ± 827 kBq for 10 min; 3709 ± 255 kBq for 30 min; 3312 ± 608 kBq for 60 min; 3645 ± 71 kBq for 120 min; 8297 ± 237 kBq for 320 min) via the lateral tail vein and allowed to awaken until sacrifice. 2 male and 2 female rats were sacrificed at each time point. Tissues and organs were collected, weighed, and counted for their radioactivity with a Packard 5550 autogamma counter. Biodistribution data were used to determine radiation-absorbed-dose estimates using the OLINDA/EXM 2.0 software package.[2,3] Distribution to the urine was determined by acquiring dynamic small animal PET scans from 0-120 min for male and female (n=2) with bladder in frame.

Results: Adrenal to background signal of sufficient quality could be obtained working within the imaging time frame for fluorine-18 (6-8 hours); consistent with work by Schwarz et. al. that demonstrated free cholesterol rapidly equilibrates with the cholesterol ester pool in the body with HDL cholesterol turnover ~6 times a day.[4] At six hours, uptake in the adrenal had increased to 11.5 percent of the injected dose per gram of tissue (%ID/g), ovary uptake increases as expected given its role in hormone synthesis, while other organ uptakes begin to decrease at 2 hours. Comparison of [¹⁸F]FNP-59 at 2 and 6 hours to NP-59 at 2 and 24 hours show [¹⁸F]FNP-59 adrenal uptake quickly reaches the maximum observed for NP-59. The adrenal to liver ratio is 9.75:1 for [¹⁸F]FNP-59 at 6 hours. Given the improved spatial resolution of fluorine-18 PET over scintiscanning or SPECT, this ratio provides the required properties for [¹⁸F]FNP-59 scans of the adrenals. Radiation dosimetry studies demonstrated that the effective dose is two orders of magnitude lower for [¹⁸F]FNP-59 compared to NP-59 with no risk to the thyroid and much reduced risk to reproductive organs.

Conclusions: The dosimetry for [¹⁸F]FNP-59 is comparable to the dose received in an FDG scan, indicating [¹⁸F]FNP-59 overcomes the dosimetry challenges that limited the use of NP-59, showing the potential of [¹⁸F]FNP-59 to be used as a non-invasive replacement for adrenal vein sampling and future applications for staging and diagnosing cholesterol related diseases like atherosclerosis. References: [1] Winton, W., Viglianti, B., Wong, KK., Scott, P., Brooks, A. J. Nucl. Med. 2020, 61 (supplement 1), 976. [2] Stabin, M. G.; Sparks, R. B.; Crowe, E. J. Nucl. Med. 2005, 46 (6), 1023-1027. [3] Stabin, M. G.; Siegel, J. A. Health Phys. 2003, 85 (3), 294-310. [4] Schwartz, C. C.; Berman, M.; Vlahcevic, Z. R.; Swell, L. J. Clin. Invest. 1982, 70 (4), 863-876. Acknowledgements: We thank Jenelle Stauff and Janna Arteaga for assistance with animal studies. This work was supported by Michigan Drug Discovery, the Michigan Medicine Department of Radiology, and a Kickstart Award from MTRAC.

• Download figure
• Open in new tab
• Download powerpoint