Pharmacokinetic assessment of the uptake of 16β-18F-fluoro- 5α-dihydrotestosterone (FDHT) in prostate tumors as measured by PET Journal Article
| Authors: | Beattie, B. J.; Smith-Jones, P. M.; Jhanwar, Y. S.; Schoder, H.; Ross Schmidtlein, C.; Morris, M. J.; Zanzonico, P.; Squire, O.; Meirelles, G. S. P.; Finn, R.; Namavari, M.; Cai, S.; Scher, H. I.; Larson, S. M.; Humm, J. L. |
| Article Title: | 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 18F-16β-fluoro-5α-dihydrotestosterone (18FFDHT) PET in prostate cancer patients undergoing therapy. Methods: Thirteen patients underwent dynamic 18F-FDHT PET over a selected tumor. Concurrent venous blood samples were acquired for blood metabolite analysis. A second cohort of 25 patients injected with 18F-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 18F-FDHT in blood was between 6 and 7 min. As a consequence, the uptake of 18F-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 18F-FDHT PET to estimate free AR concentration. This process involved the estimation of a net uptake parameter such as the ktrap 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 ktrap estimates, which we surmise may be proportional to AR expression. Validation studies to test this hypothesis are underway. Copyright © 2010 by the Society of Nuclear Medicine, Inc. |
| Keywords: | adult; clinical article; protein expression; aged; middle aged; unclassified drug; human cell; fluorouracil; positron emission tomography; prospective studies; radiopharmaceuticals; protein blood level; metastasis; cohort studies; bayes theorem; models, biological; validation study; molecular imaging; docetaxel; prostate cancer; prostatic neoplasms; drug uptake; isotope labeling; systematic review; prostate tumor; positron-emission tomography; radiopharmaceutical agent; tanespimycin; androgen receptor; bicalutamide; receptors, androgen; drug half life; oxaliplatin; 16beta fluoro 5alpha dihydrotestosterone f 18; heart; metabolite; drug binding; pharmacokinetic modeling; correlational study; pet/ct; dynamic pet; fluorine radioisotopes; fdht; radiotracer tissue kinetics; abiraterone; vein blood flow; dihydrotestosterone |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 51 |
| Issue: | 2 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2010-02-01 |
| Start Page: | 183 |
| End Page: | 192 |
| Language: | English |
| DOI: | 10.2967/jnumed.109.066159 |
| PUBMED: | 20080885 |
| PROVIDER: | scopus |
| PMCID: | PMC2866076 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "CODEN: JNMEA" - "Source: Scopus" |
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