title: Pharmacokinetic assessment of the uptake of 16beta-18F-fluoro-5alpha-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-16beta-fluoro-5alpha-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Beattie
authors.forename: Peter M
authors.initials: PM
authors.lastname: Smith-Jones
authors.forename: Yuliya S
authors.initials: YS
authors.lastname: Jhanwar
authors.forename: Heiko
authors.initials: H
authors.lastname: Schöder
authors.forename: C Ross
authors.initials: CR
authors.lastname: Schmidtlein
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morris
authors.forename: Pat
authors.initials: P
authors.lastname: Zanzonico
authors.forename: Olivia
authors.initials: O
authors.lastname: Squire
authors.forename: Gustavo S P
authors.initials: GS
authors.lastname: Meirelles
authors.forename: Ron
authors.initials: R
authors.lastname: Finn
authors.forename: Mohammad
authors.initials: M
authors.lastname: Namavari
authors.forename: Shangde
authors.initials: S
authors.lastname: Cai
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.forename: John L
authors.initials: JL
authors.lastname: Humm
mesh_terms: D000368:Aged; D015331:Cohort Studies; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006321:Heart / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D049268:Positron-Emission Tomography; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000097:blood / Q000000981:diagnostic imaging* / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: C494901:16-fluorodihydrotestosterone; C410798:AR protein, human; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D011944:Receptors, Androgen; D013196:Dihydrotestosterone