Preclinical Biodistribution and Human Radiation Dosimetry Estimates of [¹¹C]PD-132301: Imaging Sterol O-Acyltransferase to Identify Foam Cells

Objectives: PD-132301 was developed as a selective sterol O-acyltransferase 1 (SOAT1) inhibitor. SOAT1 in adrenals and macrophages is responsible for the esterification of cholesterol for storage as lipid droplets, which in macrophages lead to the formation of foam cells and atherosclerotic plaque. [¹¹C]PD-132301 has been prepared and shown to image the macrophages associated with atherosclerosis in ApoE^-/- aged mice.[1] Additionally, PD-132301 has recently been utilized in clinical studies as a treatment for adrenal diseases,[2] so the objective of this work was to determine the human radiation dosimetry estimate to facilitate clinical translation of [¹¹C]PD-132301.

Methods: [¹¹C]PD-132301 was prepared as previously described.[1] Biodistribution studies were conducted at 10, 20, 60 and 120 min post-injection in 8 male and 8 female Sprague-Dawley rats anesthetized with isoflurane (5% induction, 1-2% maintenance), and injected i.v. via the lateral tail vein. Rats were allowed to awaken until sacrifice with 2 male and 2 female rats sacrificed at each time point. Tissues and organs were collected, weighed, and counted for radioactivity with a Packard 5550 autogamma counter. Results were averaged for each time point and expressed as % injected dose/gram of tissue (%ID/g) for each organ. Small animal PET imaging studies were conducted with the bladder in frame to determine distribution to urine. OLINDA/EXM 2.0 software was utilized for the calculation of human dosimetry estimates.[3,4] Results: High adrenal uptake was observed as expected with a maximum of 2.0 %ID/g observed 10 min post injection, decreasing to 0.9 %ID/g at 2 h. The other organs with high peak uptake were the liver (1.2 %ID/g), and ovary (0.6 %ID/g). The adrenals received the second highest radiation dose at 8.92 x 10^-3 mSv/MBq, while the highest dose was observed in the small intestine (9.30 x 10^-3 mSv/MBq). The estimated effective human dose for [¹¹C]PD-132301 is 3.23 x 10^-3 mSv/MBq. Conclusion: The biodistribution study and human radiation dosimetry estimate demonstrate that [¹¹C]PD-132301 has the expected distribution given the expression of SOAT1, and it has a radiation dose in line with clinical carbon-11 PET imaging agents. This data along with the published ApoE^-/- mouse study and recent clinical study data showing the safety of PD-132301 at doses in excess of those used in PET imaging studies,[2] provides the basis for the clinical translation of [¹¹C]PD-132301 to study SOAT1 expression as a measure of atherosclerotic disease progression. References: [1] Hill, J. R.; Shao, X.; Wright, J. S.; Stauff, J.; Sherman, P. S.; Arteaga, J.; Wong, K.; Viglianti, B. L.; Scott, P. J. H.; Brooks, A. F. ACS Med. Chem. Lett. 2020, 11 (6), 1299-1304. [2] El-Maouche, D.; Merke, D. P.; Vogiatzi, M. G.; Chang, A. Y.; Turcu, A. F.; Joyal, E.; Auchus, R. J. (2020). The Journal of Clinical Endocrinology & Metabolism. 2020, 105 (8), 2771-2778. [3] Stabin, M. G.; Sparks, R. B.; Crowe, E. J. Nucl. Med. 2005, 46 (6), 1023-1027. [4] Stabin, M. G.; Siegel, J. A. Health Phys. 2003, 85 (3), 294-310. Acknowledgements: We thank Jenelle Stau! and Janna Arteaga for assistance with animal studies.

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