Sex as a Biologic Variable in Preclinical Imaging Research: Initial Observations with ¹⁸F-FLT

Abstract

The study objective was to investigate whether sex influences 3'-deoxy-3'-F-fluorothymidine (F-FLT) uptake and tissue distribution in mouse models of cancer. F-FLT biodistribution was measured in 3 strains of male and female mice (129S6/SvEv, athymic nude, and BALB/c).F-FDG biodistribution was measured for comparison. F-FLT uptake was also measured in female 129S6/SvEv mice bearing estrogen-dependent SSM3 mouse mammary tumors, male athymic nude mice bearing androgen-dependent CWR22 prostate cancer xenografts, and male and female athymic nude mice bearing estrogen-independent MDA-MB-231 human breast cancer xenografts. Ki-67 expression was assayed by immunohistochemistry. PET/CT imaging was performed to visualizeF-FLT biodistribution and to determine pharmacokinetics. GreaterF-FLT activity was observed in blood, liver, muscle, heart, kidney, and bone in female than male mice. Pharmacokinetic analysis demonstrated higher early renal F-FLT activity and greater accumulation ofF-FLT in the urinary bladder in male than female mice. The differential pattern of F-FLT biodistribution between the sexes seen withF-FLT was not observed with F-FDG. Increased tumoralF-FLT uptake compared with muscle was observed in both the SSM3 mammary tumors (2.4 ± 0.17 vs. 1.6 ± 0.14 percentage injected dose [%ID]/g at 2 h after injection, = 0.006) and the CWR22 prostate cancer xenografts (0.34 ± 0.08 vs. 0.098 ± 0.033 %ID/g at 2 h after injection, = 0.03). However, because of higher nonspecific muscle uptake in female mice, tumor-to-muscle uptake ratios were greater for CWR22 tumors than for SSM3 tumors (4.2 ± 0.78 vs. 1.5 ± 0.049 at 2 h after injection, = 0.008). Sex-dependent differences inF-FLT uptake were also observed for MDA-MB-231 xenografts (tumor-to-muscle ratio, 7.2 ± 0.9 for female vs. 16.9 ± 8.6 for male, = 0.039). Conversely, greater tumoral Ki-67 staining was observed in female mice (71% ± 3% for female vs. 54% ± 2% for male, = 0.009), and this finding more closely matched the relative differences in absolute F-FLT tumor uptake values (4.5 ± 0.99 %ID/g for female vs. 1.9 ± 0.30 %ID/g for male, = 0.03). Depending on whether female or male mice are used, differences in biodistribution and nonspecific tissue uptake can adversely affect quantitative measures ofF-FLT uptake. Thus, sex is a potential variable to consider in defining quantitative imaging metrics using F-FLT to assess tumor proliferation.

Preclinical Evaluation of Radiolabeled Peptides for PET Imaging of Glioblastoma Multiforme

“…We did not observe any substantial signal in tumors with 68 Ga-substance P. 18 F-FDG PET scan was also in the line with our ex vivo data and previously published imaging data, showing predominant accumulation of radioactivity in the heart, spleen, tumor and interscapular brown adipose tissue [23]. Similarly, data from 18 F-FLT PET imaging were in congruence with ex vivo results with the highest activity seen in the spleen, gastrointestinal tract, tumor, and largest bone tissue sites, such as knees, what confirms the findings published by Chan et al [30]. The data gained from PET acquisitions were also used for the uptake quantification of the tracers in tumor and brain regions by calculation of standardized uptake values (SUV).…”

“…Finally, 18 F-FLT exhibited relatively uniform accumulation across all studied organs (4–6% ID/g). Nevertheless, this was expected according to the literature [30]. The decrease of tracer uptake between 30 and 90 min post injection was apparent, but it was not the case for spleen, intestine, bone and tumor, On the contrary to 68 Ga-tracers, 18 F-tracers had tumor to blood ratio of 2.0.…”

The Pharmacodynamics of Antipsychotic Drugs in Women and Men

“…For instance, Okita et al (7) have shown that smoking cigarettes affects the D2 receptor to different degrees in men and women. Animal experiments have demonstrated sex effects on receptor uptake of radioactive ligands (8). One pre-clinical study has shown sex effects on the upregulation of D2 receptors after treatment with haloperidol or clozapine (9).…”

Synthesis and evaluation of 3′-[18F]fluorothymidine-5′-squaryl as a bioisostere of 3′-[18F]fluorothymidine-5′-monophosphate

“… 3,4 While we see selective uptake in paired TMPK-high and TMPK-low cells, the evidence from this work suggests that [ 18 F]SqFLT behaves more in line with an antagonist than a substrate. 26–28 Future studies of [ 18 F]SqFLT or analogues should consider how the sex of a mouse cancer model influences tumour uptake and tissue biodistribution, as previously reported for [ 18 F]FLT; 29 given the poor in vivo performance of [ 18 F]SqFLT, this was not further considered as part of this study. Incubation of [ 18 F]SqFLT with human liver microsomes (HLM) showed no metabolism over 60 min.…”