In Vivo Quantification of ERβ Expression by Pharmacokinetic Modeling: Studies with ¹⁸F-FHNP PET

The estrogen receptor (ER) is a target for endocrine therapy in breast cancer patients. Individual quantification of ERα and ERβ expression, rather than total ER levels, might enable better prediction of the response to treatment. We recently developed the tracer 2-¹⁸F-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol (¹⁸F-FHNP) for assessment of ERβ levels with PET. In the current study, we investigated several pharmacokinetic analysis methods to quantify changes in ERβ availability with ¹⁸F-FHNP PET. Methods: Male nude rats were subcutaneously inoculated in the shoulder with ERα/ERβ-expressing SKOV3 human ovarian cancer cells. Two weeks after tumor inoculation, a dynamic ¹⁸F-FHNP PET scan with arterial blood sampling was acquired from rats treated with vehicle or various concentrations of estradiol (nonspecific ER agonist) or genistein (ERβ-selective agonist). Different pharmacokinetic models were applied to quantify ERβ availability in the tumor. Results: Irreversible-uptake compartmental models fitted the kinetics of ¹⁸F-FHNP uptake better than reversible models. The irreversible 3-tissue-compartment model, which included both the parent and the metabolite input function, gave results comparable to those of the irreversible 2-tissue-compartment model with only a parent input function, indicating that radioactive metabolites contributed little to the tumor uptake. Patlak graphical analysis gave metabolic rates (K_i, the irreversible uptake rate constant) comparable to compartment modeling. The K_i values correlated well with ERβ expression but not with ERα, confirming that K_i is a suitable parameter to quantify ERβ expression. SUVs at 60 min after tracer injection also correlated (r² = 0.47; P = 0.04) with ERβ expression. A reduction in ¹⁸F-FHNP tumor uptake and K_i values was observed in the presence of estradiol or genistein. Conclusion:¹⁸F-FHNP PET enables assessment of ERβ availability in tumor-bearing rats. The most suitable parameter to quantify ERβ expression is the K_i However, a simplified static imaging protocol for determining the SUVs can be applied to assess ERβ levels.