In vivo imaging of herpes simplex virus type 1 thymidine kinase gene expression: early kinetics of radiolabelled FIAU

Previous studies have shown that the herpes simplex virus type 1 thymidine kinase gene (HSV1-tk), in combination with appropriate radiolabelled substrates (e.g. [I*]-2’-fluoro-2’-deoxy-5-iodo-1-β-d-arabinofuranosyluracil; I*-FIAU, where the asterisk indicates that any of the various radioactive iodine isotopes can be used), can be used as a reporter gene forin vivo monitoring of gene transfer and expression. The aim of our study was to examine the early kinetics of I*-FIAU and the possibility of utilising iodine-123-labelled FIAU for imaging of gene expression. CMS-5 fibrosarcoma cells were transduced in vitrowith the retroviral vector STK containing the HSV1-tk gene. BALB/c mice were inoculated subcutaneously with HSV1-tk(+) and tk(-) cells into both flanks. FAU (2’-fluoro-2’-deoxy-1-β-d-arabinofuranosyluracil was radioiodinated (¹²³I, ¹²⁵I) using the iodogen method. High-performance liquid chromatography purification resulted in high specific activity and radiochemical purity for both tracers ([¹²³I]FIAU and [¹²⁵I]FIAU). Biodistribution studies and gamma camera imaging were performed at 0.5, 1, 2 and 4 h p.i. In addition, the genomic DNA of the tumours was isolated for measurement of the activity accumulation resulting from the [¹²⁵I]FIAU incorporation. Biodistribution studies 0.5 h p.i. showed tumour/blood and tumour/muscle ratios of 3.8 and 7.2, respectively, for the HSV1-tk(+) tumours, and 0.6 and 1.2, respectively, for negative control tumours. Fast renal elimination of the tracer from the body resulted in rapidly increasing tumour/blood and tumour/muscle ratios which reached values of 32 and 88 at 4 h p.i., respectively. Tracer clearance from blood was bi-exponential, with an initial half-life of 0.6 h followed by a half-life of 4.6 h. The tracer half-life in herpes simplex viral thymidine kinase-expressing tumours was 35.7 h. The highest activity accumulation (20.3%±5.7% ID/g) in HSV1-tk(+) tumours was observed 1 h p.i. At that time, about 46% of the total activity found in HSV1-tk(+) tumours was incorporated into genomic DNA. Planar gamma camera imaging showed a distinct tracer accumulation as early as 0.5 h p.i., with an increase in contrast over time. These results suggest that sufficient tumour/background ratios for in vivo imaging of HSV1-tk expression with [¹²³I]FIAU are reached as early as 1 h p.i. Received 17 July and in revised form 12 November 1999     

In vivo imaging of herpes simplex virus type 1 thymidine kinase gene expression: early kinetics of radiolabelled FIAU

Previous studies have shown that the herpes simplex virus type 1 thymidine kinase gene (HSV1-tk), in combination with appropriate radiolabelled substrates (e.g. [I*]-2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabinofuranosyluracil, I*-FIAU, where the asterisk indicates that any of the various radioactive iodine isotopes can be used), can be used as a reporter gene for in vivo monitoring of gene transfer and expression. The aim of our study was to examine the early kinetics of I*-FIAU and the possibility of utilising iodine-123-labelled FIAU for imaging of gene expression. CMS-5 fibrosarcoma cells were transduced in vitro with the retroviral vector STK containing the HSV1-tk gene. BALB/c mice were inoculated subcutaneously with HSV1-tk(+) and tk(-) cells into both flanks. FAU (2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyluracil was radioiodinated (123I, 125I) using the iodogen method. High-performance liquid chromatography purification resulted in high specific activity and radiochemical purity for both tracers ([123I]FIAU and [125I]FIAU). Biodistribution studies and gamma camera imaging were performed at 0.5, 1, 2 and 4 h p.i. In addition, the genomic DNA of the tumours was isolated for measurement of the activity accumulation resulting from the [125I]FIAU incorporation. Biodistribution studies 0.5 h p.i. showed tumour/blood and tumour/muscle ratios of 3.8 and 7.2, respectively, for the HSV1-tk(+) tumours, and 0.6 and 1.2, respectively, for negative control tumours. Fast renal elimination of the tracer from the body resulted in rapidly increasing tumour/blood and tumour/muscle ratios which reached values of 32 and 88 at 4 h p.i., respectively. Tracer clearance from blood was bi-exponential, with an initial half-life of 0.6 h followed by a half-life of 4.6 h. The tracer half-life in herpes simplex viral thymidine kinase-expressing tumours was 35.7 h. The highest activity accumulation (20.3%+/-5.7% ID/g) in HSV1-tk(+) tumours was observed 1 h p.i. At that time, about 46% of the total activity found in HSV1-tk(+) tumours was incorporated into genomic DNA. Planar gamma camera imaging showed a distinct tracer accumulation as early as 0.5 h p.i., with an increase in contrast over time. These results suggest that sufficient tumour/background ratios for in vivo imaging of HSV1-tk expression with [123I]FIAU are reached as early as 1 h p.i.     

单纯疱疹病毒1-胸苷激酶报告基因显像研究进展

放射性核素报告基因显像技术作为监测基因治疗表达的一种有效手段,是目前研究的热点。报告基因系统主要有三类,其中酶的报告基因系统中的单纯疱疹病毒1-胸苷激酶由于其良好的理化特性,适合作为报告基因而对其进行了深入、广泛的研究,它的两类底物是嘌呤核苷衍生物和无环鸟苷衍生物,目前已经用不同放射性核素进行标记而达到显像目的。     

Comparison of [<Superscript>18</Superscript>F]FHBG and [<Superscript>14</Superscript>C]FIAU for imaging of <Emphasis Type="Italic">HSV1-tk</Emphasis> reporter gene expression: adenoviral infection vs stable transfection

Earlier studies involving comparison of different reporter probes have shown conflicting results between pyrimidine nucleosides [e.g., 2'-fluoro-2'-deoxy-1--d-arabinofuranosyl-5-iodouracil (FIAU)] and acycloguanosine derivatives [e.g., penciclovir (PCV), 9-(4-fluoro-3-hydroxymethylbutyl)guanine (FHBG)]. We hypothesized that this reported discrepancy may be related to how the reporter gene is delivered to the cells—stably transfected vs adenoviral infection. We directly compared the uptake characteristics of [¹⁸F]FHBG, [³H]PCV, and [¹⁴C]FIAU in cell culture and in vivo using an adenoviral mediated gene transfer model and stably transfected cells. We further compared the uptake of three reporter probes using both HSV1-tk and a mutant HSV1-sr39tk expressing cells to assess the optimal reporter probe/reporter gene combination. [¹⁴C]FIAU accumulation was greater than that of [³H]PCV and [¹⁸F]FHBG in control cells and in HSV1-tk stably transfected cells (P<0.001). After infection of C6 cells with AdCMV-HSV1-tk (1.5×10⁸ pfu), [¹⁸F]FHBG and [³H]PCV accumulation was significantly greater than that of [¹⁴C]FIAU (P<0.01). [¹⁸F]FHBG and [³H]PCV accumulated to a significantly greater extent than [¹⁴C]FIAU in C6-stb-sr39tk+ and AdCMV-HSV1-sr39tk infected C6 cells (P<0.001). Results from the nude mice supported the results in cell culture. [¹⁴C]FIAU led to significantly higher %ID/g in C6-stb-tk+ xenografts than [¹⁸F]FHBG (P<0.05); however, compared with [¹⁴C]FIAU, [¹⁸F]FHBG led to as high %ID/g in HSV1-tk expressing hepatocytes and to significantly greater %ID/g in C6-stb-sr39tk+ xenografts and HSV1-sr39tk expressing hepatocytes. Dynamic sequential images showed that [¹⁸F]FHBG was well retained in HSV1-sr39tk expressing cells (C6-stb-sr39tk+) for at least 4 h after injection, while it was rapidly cleared from HSV1-tk expressing cells (MH3924A-stb-tk+). [¹⁴C]FIAU accumulated in HSV1-tk stably expressing cells to a greater extent than either [³H]PCV or [¹⁸F]FHBG. However, the accumulation of [³H]PCV and [¹⁸F]FHBG in adenoviral infected C6 cells or hepatocytes was equivalent to or greater than that of [¹⁴C]FIAU. These results may be due to intracellular biochemical changes (e.g., thymidine) when cells are infected with adenovirus. For adenoviral studies, the [¹⁸F]FHBG/HSV1-sr39tk combination was shown to be more sensitive than the [¹⁴C]FIAU/HSV1-tk combination HSV1-tk.     

Molecular imaging with 123I-FIAU, 18F-FUdR, 18F-FET, and 18F-FDG for monitoring herpes simplex virus type 1 thymidine kinase and ganciclovir prodrug activation gene therapy of cancer.

The ability to monitor tumor responses during prodrug activation gene therapy and other anticancer gene therapies is critical for their translation into clinical practice. Previously, we demonstrated the feasibility of noninvasive in vivo imaging with 131I-5-iodo-2'-fluoro-1-beta-D-arabinofuranosyluracil (131I-FIAU) for monitoring herpes simplex virus type 1 thymidine kinase (HSV1-tk) cancer gene expression in an experimental animal model. Here we tested the efficacy of SPECT with 123I-FIAU and PET with 5-18F-fluoro-2'-deoxyuridine (18F-FUdR), 2-18F-fluoroethyl-L-tyrosine (18F-FET), and 18F-FDG for monitoring tumor responses during prodrug activation gene therapy with HSV1-tk and ganciclovir (GCV). METHODS: In the flanks of FVB/N female mice, 4 tumors per animal were established by subcutaneous injection of 1 x 10(5) cells of NG4TL4 sarcoma cells, HSV1-tk-transduced NG4TL4-STK cells, or a mixture of these cells in different proportions to model different efficacies of transfection and HSV1-tk gene expression levels in tumors. Ten days later, the animals were treated with GCV (10 mg/kg/d intraperitoneally) for 7 d. Gamma-Imaging with 123I-FIAU and PET with 18F-FUdR, 18F-FET, and 18F-FDG were performed before and after initiation of therapy with GCV in the same animal. RESULTS: Before GCV treatment, no significant difference in weight and size was found in tumors that expressed different HSV1-tk levels, suggesting similar in vivo proliferation rates for NG4TL4 and NG4TL4-STK sarcomas. The accumulation of 123I-FIAU at 24 h after injection was directly proportional to the percentage of NG4TL4-STK cells in the tumors. The 123I-FIAU accumulation at 4 and 7 d of GCV therapy decreased significantly compared with pretreatment levels and was proportional to the percentage of HSV1-tk-positive tumor cells. Tumor uptake of 18F-FUdR in all HSV1-tk-expressing tumors also decreased significantly compared with pretreatment levels and was proportional to the percentage of HSV1-tk-positive tumor cells. The accumulation of 18F-FET decreased minimally (about 1.5-fold) and 18F-FDG decreased only 2-fold after 7 d of GCV therapy, and the degree of reduction was proportional to the percentage of HSV1-tk-positive tumor cells. CONCLUSION: We have shown that gamma-camera imaging with 123I-FIAU was the most reliable method for prediction of tumor response to GCV therapy, which was proportional to the magnitude of HSV1-tk expression in tumor tissue. 123I-FIAU imaging can be used to verify the efficacy of elimination of HSV1-tk-expressing cells by therapy with GCV. PET with 18F-FUdR reliably visualizes proliferating tumor tissue and is most suitable for the assessment of responses in tumors undergoing HSV1-tk plus GCV prodrug activation gene therapy. PET with 18F-FDG or 18F-FET can be used as additional "surrogate" biomarkers of the treatment response, although these radiotracers are less sensitive than 18F-FUdR for monitoring tumor responses to prodrug activation gene therapy with HSV1-tk and GCV in this sarcoma model.     

Evaluation of F-18-labeled 5-iodocytidine (18F-FIAC) as a new potential positron emission tomography probe for herpes simplex virus type 1 thymidine kinase imaging

Objective

Herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene in combination with radiolabeled nucleoside substrates is the most widely used reporter system. This study characterized 1-(2′-deoxy-2′-[¹⁸F]fluoro-β-d-arabinofuranosyl)-5-iodocytosine (¹⁸F-FIAC) as a new potential positron emission tomography (PET) probe for HSV1-tk gene imaging and compared it with 2’-deoxy-2’-[¹⁸F]fluoro-5-iodo-1-β-D-arabinofuranosyluracil (¹⁸F-FIAU) and 2’-deoxy-2’-[¹⁸F]fluoro-5-ethyl-1-β-D-arabinofuranosyluracil(¹⁸F-FEAU) (thymidine analogues) in an NG4TL4-WT/STK sarcoma-bearing mouse model.

Methods

A cellular uptake assay, biodistribution study, radioactive metabolites assay and microPET imaging of NG4TL4-WT/STK tumor-bearing mice post administration of ¹⁸F-FIAC, ¹⁸F-FIAU and ¹⁸F-FEAU were conducted to characterize the biological properties of these tracers.

Results

Highly specific uptake of ¹⁸F-FIAC, ¹⁸F-FIAU and ¹⁸F-FEAU in tk-transfected [tk(+)] cells was observed. The tk(+)-to-tk(−) cellular uptake ratio after a 2-h incubation was 66.6±25.1, 76.3±18.2 and 247.2±37.2, respectively. In biodistribution studies, ¹⁸F-FIAC showed significant tk(+) tumor specificity (12.6; expressed as the tk(+)-to-tk(−) tumor uptake ratio at 2 h postinjection) comparable with ¹⁸F-FIAU (15.8) but lower than ¹⁸F-FEAU (48.0). The results of microPET imaging also revealed the highly specific accumulation of these three radioprobes in the NG4TL4-tk(+) tumor.

Conclusion

Our findings suggested that the cytidine analogue ¹⁸F-FIAC is a new potential PET probe for the imaging of HSV1-tk gene expression. ¹⁸F-FIAC may be regarded as the prodrug of ¹⁸F-FIAU in vivo.     

Comparison of [18F]FHPG and [124/125I]FIAU for imaging herpes simplex virus type 1 thymidine kinase gene expression.

Various radiotracers based on uracil nucleosides (e.g. [124I]2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabinofuranosyluracil, [124I]FIAU) and acycloguanosine derivatives (e.g. [18F]9-[(3-fluoro-1-hydroxy-2-propoxy) methyl] guanine, [18F]FHPG) have been proposed for the non-invasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene expression. However, these radiotracers have been evaluated in different in vitro and in vivo models, precluding a direct comparison. Therefore, we directly compared [18F]FHPG and radioiodinated FIAU to assess their potential for PET imaging of transgene expression. The uptake of [125I]FIAU, [18F]FHPG and [3H]acyclovir was determined in vitro using four different HSV1-tk expressing cell lines and their respective negative controls. The in vitro tracer uptake was generally low in non-transduced parental cell lines. In HSV1-tk expressing cells, [3H]acyclovir showed approximately a twofold higher tracer accumulation, the [18F]FHPG uptake increased by about sixfold and the [125I]FIAU accumulation increased by about 28-fold after 120-min incubation of T1115 human glioblastoma cells. Similar results were found in the other cell lines. In addition, biodistribution and positron emission tomography (PET) studies with [18F]FHPG and [124/125I]FIAU were carried out in tumour-bearing BALB/c mice. Significantly higher specific accumulation of radioactivity was found for [125I]FIAU compared with [18F]FHPG. The ratio of specific tracer accumulation between [125I]FIAU and [18F]FHPG increased from 21 (30 min p.i.) to 119 (4 h p.i.). PET imaging, using [124I]FIAU, clearly visualised and delineated HSV1-tk expressing tumours, whereas only a negligible uptake of [18F]FHPG was observed. This study demonstrated that in vitro and in vivo, the radioiodinated uracil nucleoside FIAU has a significantly higher specific accumulation than the acycloguanosine derivative [18F]FHPG. This suggests that [124I]FIAU should be the preferred reporter probe for PET imaging of HSV1-tk gene expression. Thus, further attempts to develop suitable PET tracers for the assessment of HSV1-tk gene expression should also focus on 18F-labelled uracil derivatives.     

HSV-TK/GCV自杀基因系统联合γ射线放射治疗宫颈癌的实验研究

目的 探讨HSV-TK／GCV自杀基因系统协同^60Coγ射线放射治疗对人宫颈癌细胞系的体内外联合杀伤作用，以及HSV-TK／GCV对放射治疗的增敏作用。方法 分别以HSV-TK／GCV、^60Coγ射线放射治疗及两者联合治疗人宫颈癌HeLa细胞系和裸鼠宫颈癌移植瘤模型，比较治疗效果；利用增敏效应比值（E／O）、克隆形成实验评价体内外HSV-TK／GCV对放射敏感性的影响。结果 在体外实验中，自杀基因对宫颈癌HeLa细胞生长的抑制率为45．8％，单纯放疗的抑制率为42．4％，而基因治疗与放疗联用的抑制率为87．5％，与前两者比较，差异有统计学意义（P〈0．01）；且联合治疗组对射线敏感性较单独治疗组明显增加，克隆形成率明显下降（P〈0．05）；在体内实验中，单纯基因治疗与放疗对HeLa细胞裸鼠皮下移植瘤生长的抑瘤率分别为39．5％和35．8％，而基因治疗放疗联用的抑瘤率达到87．9％，与前两者比较，差异均有统计学意义（P〈0．01）；增敏效应比值（E／O）为3．2（〉1．4），提示HSV-TK／GCV对放疗具有增敏作用。结论 HSV-TK／GCV自杀基因系统具有放射增敏作用，二者联合治疗可作为宫颈癌综合治疗的有效补充方法。     

O-[18F]fluoromethyl-L-tyrosine is a potential tracer for monitoring tumour response to chemotherapy using PET: an initial comparative in vivo study with deoxyglucose and thymidine

Purpose To compare the utility of a new artificial amino acid, O-[¹⁸F]fluoromethyl-L-tyrosine ([¹⁸F]FMT), for monitoring cancer chemotherapy with deoxyglucose and thymidine.Methods [¹⁸F]FMT, [¹⁴C]deoxyglucose ([¹⁴C]DG) and [6-³H]thymidine ([³H]Thd) were applied in this study. A 2.5 mg/kg dose of mitomycin (MMC) was administered to AH272 rat hepatoma-bearing Donryu rats. Tumour uptake of each tracer was measured just before (baseline) and on days 1, 3, 5 and 7 after the MMC administration, 1 h after a mixture of [¹⁸F]FMT, [¹⁴C]DG and [³H]Thd had been injected, and was shown as DURs (% injected dose/gram tissue normalised for the rat body weight). Dual-tracer macroautoradiographs with [¹⁸F]FMT and [¹⁴C]DG were also prepared.Results The tumour uptake for each tracer decreased earlier than did the tumour size. DURs (mean±SD) at baseline and on days 1, 3, 5 and 7 were as follows: [¹⁸F]FMT: 4.68±0.72, 3.34±0.66, 3.13±0.72, 3.42±0.45, 3.01±0.32; [¹⁴C]DG: 3.26±0.40, 3.09±0.55, 3.01±0.97, 2.28±0.35, 1.70±0.72; and [³H]Thd: 2.23±0.46, 1.54±0.45, 1.28±0.37, 1.35±0.20, 0.94±0.12. Decrease in [¹⁸F]FMT uptake compared with baseline was significant from day 1 (p<0.01), and the decrease in [³H]Thd uptake was also significant on day 1 (p<0.05) and days 3–7 (p<0.01). However, decrease in [¹⁴C]DG uptake was only significant from day 5 (p<0.01). Macroautoradiography suggested that the influence of inflammatory cells on the accumulation of [¹⁸F]FMT in tumours is smaller than that on the accumulation of [¹⁴C]DG.Conclusion [¹⁸F]FMT uptake shows a rapid and sensitive response to chemotherapy, comparable to that of [³H]Thd, suggesting that it may be applied as a powerful tracer for monitoring of proliferative activity after cancer chemotherapy using PET.     

A new acycloguanosine-specific supermutant of herpes simplex virus type 1 thymidine kinase suitable for PET imaging and suicide gene therapy for potential use in patients treated with pyrimidine-based cytotoxic drugs.

The herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene is widely used as a suicide gene in combination with ganciclovir (GCV) and as a nuclear imaging reporter gene with an appropriate reporter probe. Wild-type HSV1-tk recognizes a variety of pyrimidine and acycloguanosine nucleoside analogs, including clinically used antiviral drugs. PET of HSV1-tk reporter gene expression will be compromised in patients receiving nucleoside-based antiviral treatment. With the use of an acycloguanosine-specific mutant of the enzyme, PET of HSV1-tk reporter gene expression can be successfully performed with acycloguanosine-based radiotracers without interference from pyrimidine-based antiviral drugs. METHODS: The levels of expression of wild-type HSV1-tk and HSV1-A167Ytk, HSV1-sr39tk, and HSV1-A167Ysr39tk mutants fused with green fluorescent protein (GFP) and transduced into U87 cells were normalized to the mean fluorescence of GFP measured by fluorescence-activated cell sorting. The levels of enzymatic activities of wild-type HSV1-tk and its mutants were compared by 2-h in vitro radiotracer uptake assays with (3)H-2'-fluoro-2'-deoxy-1-beta-d-arabinofuranosyl-5-ethyluracil ((3)H-FEAU), (3)H-pencyclovir ((3)H-PCV), and (3)H-GCV and by drug sensitivity assays. PET with (18)F-FEAU and (18)F-9-[4-fluoro-3-(hydroxymethyl)butyl]guanine ((18)F-FHBG) was performed in mice with established subcutaneous tumors, expressing wild-type HSV1-tk and its mutants, followed by tissue sampling. RESULTS: FEAU accumulation was not detected in HSV1-A167Ysr39tk-expressing cells and xenografts. Lack of conversion of pyrimidine derivatives by the HSV1-A167Ysr39tk supermutant was also confirmed by a drug sensitivity assay, in which the 50% inhibitory concentrations for thymine 1-beta-d-arabinofuranoside and bromovinyldeoxyuridine were found to be similar to those in nontransduced cells. In contrast, we found that HSV1-A167Ysr39tk could readily phosphorylate (3)H-GCV at levels similar to those of wild-type HSV1-tk and HSV1-A167Ytk but showed enhanced activity with (3)H-PCV in vitro and with (18)F-FHBG in vivo. CONCLUSION: We developed a new reporter gene, HSV1-A167Ysr39tk, which exhibits specificity and high phosphorylation activity for acycloguanosine derivatives. The resulting supermutant can be used for PET with (18)F-FHBG and suicidal gene therapy protocols with GCV in patients treated with pyrimidine-based cytotoxic drugs.     

Comparisons of [18F]-1-deoxy-1-fluoro-scyllo-inositol with [18F]-FDG for PET imaging of inflammation, breast and brain cancer xenografts in athymic mice

Introduction

The aim of the study was to evaluate the uptake of [¹⁸F]-1-deoxy-1-fluoro-scyllo-inositol ([¹⁸F]-scyllo-inositol) in human breast cancer (BC) and glioma xenografts, as well as in inflammatory tissue, in immunocompromised mice. Studies of [¹⁸F]-2-fluoro-2-deoxy-d-glucose ([¹⁸F]-FDG) under the same conditions were also performed.

Methods

Radiosynthesis of [¹⁸F]-scyllo-inositol was automated using a commercial synthesis module. Tumour, inflammation and normal tissue uptakes were evaluated by biodistribution studies and positron emission tomography (PET) imaging using [¹⁸F]-scyllo-inositol and [¹⁸F]-FDG in mice bearing subcutaneous MDA-MB-231, MCF-7 and MDA-MB-361 human BC xenografts, intracranial U-87 MG glioma xenografts and turpentine-induced inflammation.

Results

The radiosynthesis of [¹⁸F]-scyllo-inositol was automated with good radiochemical yields (24.6%±3.3%, uncorrected for decay, 65±2 min, n=5) and high specific activities (≥195 GBq/μmol at end of synthesis). Uptake of [¹⁸F]-scyllo-inositol was greatest in MDA-MB-231 BC tumours and was comparable to that of [¹⁸F]-FDG (4.6±0.5 vs. 5.5±2.1 %ID/g, respectively; P=.40), but was marginally lower in MDA-MB-361 and MCF-7 xenografts. Uptake of [¹⁸F]-scyllo-inositol in inflammation was lower than [¹⁸F]-FDG. While uptake of [¹⁸F]-scyllo-inositol in intracranial U-87 MG xenografts was significantly lower than [¹⁸F]-FDG, the tumour-to-brain ratio was significantly higher (10.6±2.5 vs. 2.1±0.6; P=.001).

Conclusions

Consistent with biodistribution studies, uptake of [¹⁸F]-scyllo-inositol was successfully visualized by PET imaging in human BC and glioma xenografts, with lower accumulation in inflammatory tissue than [¹⁸F]-FDG. The tumour-to-brain ratio of [¹⁸F]-scyllo-inositol was also significantly higher than that of [¹⁸F]-FDG for visualizing intracranial glioma xenografts in NOD SCID mice, giving a better contrast.     

[<Superscript>11</Superscript>C]Choline uptake with PET/CT for the initial diagnosis of prostate cancer: relation to PSA levels,tumour stage and anti-androgenic therapy

PURPOSE: The accuracy of positron emission tomography (PET)/CT with [(11)C]choline for the detection of prostate cancer is not well established. We assessed the dependence of [(11)C]choline maximum standardized uptake values (SUV(max)) in the prostate gland on cell malignancy, prostate-specific antigen (PSA) levels, Gleason score, tumour stage and anti-androgenic hormonal therapy. METHODS: In this prospective study, PET/CT with [(11)C]choline was performed in 19 prostate cancer patients who subsequently underwent prostatectomy with histologic sextant analysis (group A) and in six prostate cancer patients before and after anti-androgenic hormonal therapy (bicalutamide 150 mg/day; median treatment of 4 months; group B). RESULTS: In group A, based on a sextant analysis with a [(11)C]choline SUV(max) cutoff of 2.5 (as derived from a receiver-operating characteristic analysis), PET/CT showed sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 72, 43, 64, 51 and 60%, respectively. In the patient-by-patient analysis, no significant correlation was detected between SUV(max) and PSA levels, Gleason score or pathological stage. On the contrary, a significant (P < 0.05) negative correlation was detected between SUV(max) and anti-androgenic therapy both in univariate (r (2) = 0.24) and multivariate (r (2) = 0.48) analyses. Prostate [(11)C]choline uptake after bicalutamide therapy significantly (P < 0.05) decreased compared to baseline (6.4 +/- 4.6 and 11.8 +/- 5.3, respectively; group B). CONCLUSION: PET/CT with [(11)C]choline is not suitable for the initial diagnosis and local staging of prostate cancer. PET/CT with [(11)C]choline could be used to monitor the response to anti-androgenic therapy.