Pharmacokinetic Assessment of the Uptake of 16β-¹⁸F-Fluoro-5α-Dihydrotestosterone (FDHT) in Prostate Tumors as Measured by PET

Abstract

The aim of this study was to develop a clinically applicable noninvasive method to quantify changes in androgen receptor (AR) levels based on 18 F-16b-fluoro-5a-dihydrotestosterone ( 18 F-FDHT) PET in prostate cancer patients undergoing therapy. Methods: Thirteen patients underwent dynamic 18 F-FDHT PET over a selected tumor. Concurrent venous blood samples were acquired for blood metabolite analysis. A second cohort of 25 patients injected with 18 F-FDHT underwent dynamic PET of the heart. These data were used to generate a population-based input function, essential for pharmacokinetic modeling. Linear compartmental pharmacokinetic models of increasing complexity were tested on the tumor tissue data. Four suitable models were applied and compared using the Bayesian information criterion (BIC). Model 1 consisted of an instantaneously equilibrating space, followed by a unidirectional trap. Models 2a and 2b contained a reversible space between the instantaneously equilibrating space and the trap, into which metabolites were excluded (2a) or allowed (2b). Model 3 built on model 2b with the addition of a second reversible space preceding the unidirectional trap and from which metabolites were excluded. Results: The half-life of the 18 F-FDHT in blood was between 6 and 7 min. As a consequence, the uptake of 18 F-FDHT in prostate cancer lesions reached a plateau within 20 min as the blood-borne activity was consumed. Radiolabeled metabolites were shown not to bind to ARs in in vitro studies with CWR22 cells. Model 1 produced reasonable and robust fits for all datasets and was judged best by the BIC for 16 of 26 tumor scans. Models 2a, 2b, and 3 were judged best in 7, 2, and 1 cases, respectively. Conclusion: Our study explores the clinical potential of using 18 F-FDHT PET to estimate free AR concentration. This process involved the estimation of a net uptake parameter such as the k trap of model 1 that could serve as a surrogate measure of AR expression in metastatic prostate cancer. Our initial studies suggest that a simple body mass-normalized standardized uptake value correlates reasonably well to model-based k trap estimates, which we surmise may be proportional to AR expression. Validation studies to test this hypothesis are underway.

Image-Derived Input Function for Brain PET Studies: Many Challenges and Few Opportunities

“…Population-based input function has been validated mostly for [ 18 F]-FDG, using arterial (Takikawa et al, 1993) or venous blood samples (Takagi et al, 2004) as scaling factors, or using noninvasive individual parameters such as body surface area (Shiozaki et al, 2000) or cerebellar [ 18 F]-FDG activity (Bentourkia, 2006). Studies with other PET tracers are very rare (Beattie et al, 2010;Cook et al, 1999;Takikawa et al, 1994). Nevertheless, PBIF appears to have many practical advantages over IDIF, especially for brain studies where IDIF is more challenging to obtain.…”

Bone Metastases in Castration-Resistant Prostate Cancer: Associations between Morphologic CT Patterns, Glycolytic Activity, and Androgen Receptor Expression on PET and Overall Survival

“…Data in parentheses are percentages. 5,19). On the other hand, FDG uptake in cancer is mediated by the Warburg effect, where FDG is trapped within tumor cells with a relatively high glycolytic rate; however, FDG uptake is neither specific to nor invariably present in cancer cells, and it may also occur in other inflammatory conditions (20).…”

“…The diversity of metabolic phenotypes of bone metastases in patients with castration-resistant prostate cancer, potentially evidenced by discordance between FDG and FDHT uptake, was previously documented (5,18). As an analog of the primary ligand of the androgen receptor, FDHT is part of a novel group of PET tracers with specific relevance to castration-resistant prostate cancer (5,19). In vivo quantitative kinetic models of FDHT uptake as a measure of androgen receptor expression and displacement of FDHT by antiandrogen therapy have been majority of bone metastases in prostate cancer occur in the pelvis and spine and have a dense osteoblastic pattern.…”

Evaluation of Castration-Resistant Prostate Cancer with Androgen Receptor–Axis Imaging

“…One final point: new targeting agents have recently been approved by the Food and Drug Administration, such as 18 F-fluciclovine (60), 11 C-choline (61), and 68 Ga-PSMA (59). All of these agents provide high-quality images and are documented to be useful for imageguided biopsy to detect occult tumors, especially in PSA recurrence after primary treatment of prostate cancer.…”

“…Beattie et al applied linear compartmental pharmacokinetic modeling to 18 F-FDHT uptake into tumor to a simple 2-compartment model in which the destination compartment was considered a permanent, unidirectional parameter, k trap , attributed to intramolecular transport and binding to AR; a population-based input function was calculated by averaging aorta region-of-interest data from dynamic PET scans of a 25-patient cohort (11) (Fig. 2B).…”