In vitro and in vivo antitumor properties of tetrakis((trishydroxy- methyl)phosphine)gold(I) chloride

A novel hydrophilic gold compound, tetrakis((trishydroxymethyl)phosphine)gold(I) chloride 1, has been investigated for its antitumor properties. In vitro studies demonstrate that 1 is active against HCT-15, AGS, PC-3, and LNCaP tumor cells. Cell cycle analysis of the HCT-15 cells by flow cytometry revealed elongation of the G1 phase of the cell cycle leading to growth inhibition. Administration of 1 to Balb/C mice inoculated with syngenic meth/A cells demonstrated statistically significant dose-dependent survival time.     

Syntheses, in vitro and in vivo characterization of a 99mTc-(I)-tricarbonyl-benzylamino-dihydroxymethyl phosphine (NP(2)) chelate.

Studies were performed to study the complexation chemistry of 99mTc(CO)(+)(3) with a new tridentate amino-dihydroxymethyl phosphine (NP(2)) ligand with the 99mTc(CO)(3)(OH(2))(+)(3) synthon at tracer levels. A single, well-defined 99mTc(CO)(3)NP(2) complex is formed at pH 7.5 within 10 min at 60 degrees C that exhibits high in vitro and in vivo stability.     

Repeatability of [<Superscript>68</Superscript>Ga]DKFZ11-PSMA PET Scans for Detecting Prostate-specific Membrane Antigen-positive Prostate Cancer

Purpose

We studied the effect of varying specific activity of [⁶⁸Ga]DKFZ-PSMA11 ([⁶⁸Ga]DP11) on repeated imaging of prostate-specific membrane antigen-positive (PSMA+) xenograft tumors.

Procedures

Athymic nude mice bearing PC3-PIP (PSMA+) and PC3 (PSMA?) bilateral flank tumors were assessed to study intra- and inter-day repeatability of [⁶⁸Ga]DP11 imaging in mice administered [⁶⁸Ga]DP11 or [⁶⁷Ga]DP11 (as a dilution tracer) using imaging and biodistribution studies.

Results

Region of interest (ROI) analysis of the [⁶⁸Ga]DP11 imaging study indicated that the uptake was constant on the same day or consecutive days. Prior imaging with [⁶⁸Ga]DP11 did not significantly influence the subsequent uptake of [⁶⁸Ga]DP11. Uptake of [⁶⁸Ga]DP11 (60 min) and [⁶⁷Ga]DP11 (24 h) in PC3-PIP tumors was 12.37 ± 4.19 %ID/g and 12.49 ± 6.88 %ID/g, respectively; [⁶⁸Ga]DP11 was 13.83 ± 3.77 and 17.76 ± 1.84 on same-day and 15.98 ± 5.82 %ID/g on second-day imaging.

Conclusions

This study demonstrates that [⁶⁸Ga]DP11, in a given PSMA+ lesion, is constant under several same-day or serial-day imaging conditions.

     

Radiosynthesis of the iodine‐124 labeled Hsp90 inhibitor PU‐H71

Heat shock protein 90 (Hsp90) is an ATP dependent molecular chaperone protein whose function is critical for maintaining several key proteins involved in survival and proliferation of cancer cells. PU‐H71 (1), is a potent purine‐scaffold based ATP pocket binding Hsp90 inhibitor which has been shown to have potent activity in a broad range of in vivo cancer models and is currently in Phase I clinical trials in patients with advanced solid malignancies, lymphomas, and myeloproliferative neoplasms. In this report, we describe the radiosynthesis of [¹²⁴I]‐PU‐H71(5); this was synthesized from the corresponding Boc‐protected stannane precursor 3 by iododestannylation with [¹²⁴I]‐NaI using chloramine‐T as an oxidant for 2 min, followed by Boc deprotection with 6 N HCl at 50 °C for 30 min to yield the final compound. The final product 5 was purified using HPLC and was isolated with an overall yield of 55 ± 6% (n = 6, isolated) from 3, and >98% purity and an average specific activity of 980 mCi/µmol. Our report sets the stage for the introduction of [¹²⁴I]‐PU‐H71 as a potential non‐invasive probe for understanding biodistribution and pharmacokinetics of PU‐H71 in living subjects using positron emission tomography imaging.     

Antilipolytic drug boosts glucose metabolism in prostate cancer

IntroductionThe antilipolytic drug Acipimox reduces free fatty acid (FFA) levels in the blood stream. We examined the effect of reduced FFAs on glucose metabolism in androgen-dependent (CWR22Rv1) and androgen-independent (PC3) prostate cancer (PCa) xenografts.MethodsSubcutaneous tumors were produced in nude mice by injection of PC3 and CWR22Rv1 PCa cells. The mice were divided into two groups (Acipimox vs. controls). Acipimox (50 mg/kg) was administered by oral gavage 1 h before injection of tracers. 1 h after i.v. co-injection of 8.2 MBq (222 ± 6.0 μCi) ¹⁸ F-FDG and ~ 0.0037 MBq (0.1 μCi) ¹⁴C-acetate, ¹⁸ F-FDG imaging was performed using a small-animal PET scanner. Counting rates in reconstructed images were converted to activity concentrations. Quantification was obtained by region-of-interest analysis using dedicated software. The mice were euthanized, and blood samples and organs were harvested. ¹⁸ F radioactivity was measured in a calibrated γ-counter using a dynamic counting window and decay correction. ¹⁴C radioactivity was determined by liquid scintillation counting using external standard quench corrections. Counts were converted into activity, and percentage of the injected dose per gram (%ID/g) tissue was calculated.ResultsFDG biodistribution data in mice with PC3 xenografts demonstrated doubled average %ID/g tumor tissue after administration of Acipimox compared to controls (7.21 ± 1.93 vs. 3.59 ± 1.35, P = 0.02). Tumor-to-organ ratios were generally higher in mice treated with Acipimox. This was supported by PET imaging data, both semi-quantitatively (mean tumor FDG uptake) and visually (tumor-to-background ratios). In mice with CWR22Rv1 xenografts there was no effect of Acipimox on FDG uptake, either in biodistribution or PET imaging. ¹⁴C-acetate uptake was unaffected in PC3 and CWR22Rv1 xenografts.ConclusionsIn mice with PC3 PCa xenografts, acute administration of Acipimox increases tumor uptake of ¹⁸ F-FDG with general improvements in tumor-to-background ratios. Data indicate that administration of Acipimox prior to ¹⁸ F-FDG PET scans has potential to improve sensitivity and specificity in patients with castration-resistant advanced PCa.     

An improved strategy for the synthesis of [18F]-labeled arabinofuranosyl nucleosides

The expression of the herpes simplex virus type-1 thymidine kinase (HSV1-tk) gene can be imaged efficaciously using a variety of 2′-[¹⁸F]fluoro-2′-deoxy-1-b-D-arabinofuranosyl-uracil derivatives [[¹⁸F]-FXAU, X = I(iodo), E(ethyl), and M(methyl)]. However, the application of these derivatives in clinical and translational studies has been impeded by their complicated and long syntheses (3–5 h). To remedy these issues, in the study at hand we have investigated whether microwave or combined catalysts could facilitate the coupling reaction between sugar and nucleobase and, further, have probed the feasibility of establishing a novel approach for [¹⁸F]-FXAU synthesis.We have demonstrated that the rate of the trimethylsilyl trifluoromethanesulfonate (TMSOTf)-catalyzed coupling reaction between the 2-deoxy-sugar and uracil derivatives at 90 °C can be significantly accelerated by microwave-driven heating or by the addition of Lewis acid catalyst (SnCl₄). Further, we have observed that the stability of the α- and β-anomers of [¹⁸F]-FXAU derivatives differs during the hydrolysis step. Using the microwave-driven heating approach, overall decay-corrected radiochemical yields of 19%–27% were achieved for [¹⁸F]-FXAU in 120 min at a specific activity of > 22 MBq/nmol (595 Ci/mmol). Ultimately, we believe that these high yielding syntheses of [¹⁸F]-FIAU, [¹⁸F]-FMAU and [¹⁸F]-FEAU will facilitate routine production for clinical applications.     

Synthesis and evaluation of [18F] labeled pyrimidine nucleosides for positron emission tomography imaging of herpes simplex virus 1 thymidine kinase gene expression

Synthesis of three novel 2'-deoxy-2'-[18F]fluoro-1-beta-D-arabinofuranosyluracil derivatives [18F]FPAU, [18F]FBrVAU, and [18F]FTMAU is reported. The compounds were synthesized by coupling of 1-bromo-2-deoxy-2-fluoro sugars with corresponding silylated uracil derivatives. In vitro cell uptake indicated that all three compounds are taken up selectively in RG2TK+ cells with negligible uptake in RG2 cells. The results indicate that [18F]FBrVAU and [18F]FTMAU have better uptake profiles in comparison to [18F]FPAU and have potential as PET probes for imaging HSV1-tk gene expression.     

Dosimetry of 18F-Labeled Tyrosine Kinase Inhibitor SKI-249380, a Dasatinib-Tracer for PET Imaging

Purpose  

To obtain estimates of human normal-organ radiation doses of ¹⁸F-SKI-249380, as a prerequisite step towards first-in-human trial. ¹⁸F-SKI-249380 is a first-of-its-kind PET tracer for imaging the in vivo pharmacokinetics of dasatinib, an investigational targeted therapy for solid malignancies.     

Tumor-Specific Targeting With Modified Sindbis Viral Vectors: Evaluation with Optical Imaging and Positron Emission Tomography In Vivo

Purpose

Sindbis virus (SINV) infect tumor cells specifically and systemically throughout the body. Sindbis vectors are capable of expressing high levels of transduced suicide genes and thus efficiently produce enzymes for prodrug conversion in infected tumor cells. The ability to monitor suicide gene expression levels and viral load in patients, after administration of the vectors, would significantly enhance this tumor-specific therapeutic option.

Procedures

The tumor specificity of SINV is mediated by the 67-kDa laminin receptor (LR). We probed different cancer cell lines for their LR expression and, to determine the specific role of LR-expression in the infection cycle, used different molecular imaging strategies, such as bioluminescence, fluorescence molecular tomography, and positron emission tomography, to evaluate SINV-mediated infection in vitro and in vivo.

Results

All cancer cell lines showed a marked expression of LR. The infection rates of the SINV particles, however, differed significantly among the cell lines.

Conclusion

We used novel molecular imaging techniques to visualize vector delivery to different neoplatic cells. SINV infection rates proofed to be not solely dependent on cellular LR expression. Further studies need to evaluate the herein discussed ways of cellular infection and viral replication.