Pharmacodynamic imaging guides dosing of a selective estrogen receptor degrader.

PURPOSE: Estrogen receptor (ER) targeting is key in management of receptor-positive breast cancer. Currently, there are no methods to optimize anti-ER therapy dosing. This study assesses the use of 16α-(18)F-fluoroestradiol ((18)F-FES) PET for fulvestrant dose optimization in a preclinical ER(+) breast cancer model. EXPERIMENTAL DESIGN: In vitro, (18)F-FES retention was compared with ERα protein expression (ELISA) and ESR1 mRNA transcription (qPCR) in MCF7 cells (ER(+)) after treatment with different fulvestrant doses. MCF7 xenografts were grown in ovariectomized nude mice and assigned to vehicle, low- (0.05 mg), medium- (0.5 mg), or high-dose (5 mg) fulvestrant treatment groups (5-7 per group). Two and 3 days after fulvestrant treatment, PET/CT was performed using (18)F-FES and (18)F-FDG, respectively. ER expression was assessed by immunohistochemistry, ELISA, and qPCR on xenografts. Tumor proliferation was assessed using Ki67 immunohistochemistry. RESULTS: In vitro, we observed a parallel graded reduction in (18)F-FES uptake and ER expression with increased fulvestrant doses, despite enhancement of ER mRNA transcription. In xenografts, ER expression significantly decreased with increased fulvestrant dose, despite similar mRNA expression and Ki67 staining among the treatment groups. We observed a significant dose-dependent reduction of (18)F-FES PET mean standardized uptake value (SUV(mean)) with fulvestrant treatment but no significant difference among the treatment groups in (18)F-FDG PET SUV(mean). CONCLUSIONS: We demonstrated that (18)F-FES uptake mirrors the dose-dependent changes in functional ER expression with fulvestrant resulting in ER degradation and/or blockade; these precede changes in tumor metabolism and proliferation. Quantitative (18)F-FES PET may be useful for tracking early efficacy of ER blockade/degradation and guiding ER-targeted therapy dosing in patients with breast cancer.

A container closure system that allows for greater recovery of radiolabeled peptide compared to the standard borosilicate glass system.

OBJECTIVES: Often peptides used in synthesis of radiopharmaceutical PET tracers are lipophilic and adhere to the walls of container closure systems (CCS) such that costly peptide and product are not fully recoverable after synthesis occurs. This investigation compares a standard United States Pharmacopeia (USP) Type I borosilicate glass CCS to a cyclic polyolefin copolymer Crystal Zenith(®) (CZ) CCS, for (68)Ga-chloride and (68)Ga-DOTATOC ([(68)Ga] Ga-DOTA-D-Phe1-Tyr3-octreotide) retention in the reaction vial after labeling. METHODS: (68)Gallium labeling of DOTATOC was conducted by adding (68)Ga-chloride, 2M HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid) or 0.75 M sodium acetate, and 1-30 µg of DOTATOC into the CZ or glass CCS. The reaction mixture was heated for 15 min and cooled to room temperature. The crude reaction mixture was then withdrawn via syringe, for final processing. The CCS was then assayed using a dose calibrator to determine the amount of retained (68)Ga-DOTATOC. Statistical significance was assessed using an unpaired Student's t-test. RESULTS: In all experiments (n=72) with various amounts of peptide and different buffering systems, the CZ CCS retained less activity than the glass CCS. Using 2 M HEPES and 15 µg or 30 µg of DOTATOC, the CZ CCS retained approximately 10% less of the labeled DOTATOC compared to the glass CCS (p<0.05). Utilizing either a sodium acetate or a HEPES buffering system with 15 µg or 30 µg of DOTATOC, the CZ CCS retained approximately 2.5% less of the total reaction activity compared to the glass CCS (p<0.05). Product yield was equivalent in glass and CZ CCS under the same reaction conditions. Both the CZ and glass vials showed no retention of (68)Ga-chloride. CONCLUSION: For applications involving the labeling of peptides such as (68)Ga-DOTATOC, the CZ CCS compared to the glass CCS, results in an improved recovery of product.

Microfluidic single vessel production of hypoxia tracer 1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitro-imidazole ([18F]-FMISO).

We report an automated synthesis of [(18)F]-FMISO utilizing a prototype microfluidic radiochemistry module. The instrument allows for production of the tracer with 58%±2% (11 runs) decay corrected yield. Total time of production, including synthesis and purification averages 60 min. Use of the microfluidic platform results in a specific activity of 138.6 GBq/µ mol, which is higher than previously reported for conventional reactors.