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The aim of this study was to formulate and evaluate the freeze‐dried kit of NOTA‐hexavalent lactoside (NOTA‐HL) for the preparation of 68Ga‐labeled glycoligand for PET imaging of the asialoglycoprotein receptor (ASGPR). 68GaCl3 was obtained from a commercial 68Ge/68Ga generator. Single‐vial kits of HL were formulated. Optimization of radiolabeling with 68Ga, various evaluations of NOTA‐HL kits, and in vitro stability study of 68Ga‐HL were carried out. PET/CT imaging of normal mice injected with 68Ga‐NOTA‐HL was performed. NOTA‐HL kit was successfully formulated. High radiochemical yields (>95%) were obtained by 68Ga radiolabeling. The NOTA‐HL kits were stable for at least 12 months, and 68Ga‐NOTA‐HL exhibited good in vitro stability. PET studies in normal mice revealed high specific accumulation of activity in the liver. The NOTA‐HL kit was developed for fast 68Ga labeling. 68Ga‐NOTA‐HL showed high specific uptake in liver. The availability of ready‐to‐use NOTA‐HL kits combined with 68Ge/68Ga generators would provide an efficient approach for PET imaging of ASGPR. The freeze‐dried kit of NOTA‐hexavalent lactoside (NOTA‐HL) was formulated for the preparation of 68Ga‐NOTA‐HL for PET imaging of the asialoglycoprotein receptor (ASGPR). High radiochemical yields (>95%) were obtained. The NOTA‐HL kits were stable for at least 12 months, and 68Ga‐NOTA‐HL exhibited good in vitro stability. PET studies in normal mice revealed high specific accumulation of activity in the liver. The availability of ready‐to‐use NOTA‐HL kits combined with 68Ge/68Ga generators would provide an efficient approach for PET imaging of ASGPR. [ABSTRACT FROM AUTHOR]

Radiolabeled Arg-Gly-Asp (RGD) peptide analogs have been extensively studied for αvβ3 integrin-targeted angiogenesis imaging. According to recently presented evidence, the dodecapeptide GE11 has high affinity to the epidermal growth factor receptor (EGFR), which is overexpressed in many types of cancer. Dual-receptor molecular imaging probes with two different heterodimeric peptides exhibit improved cancer targeting efficacy. In the present study, the design and synthesis of a new RGD-GE11 peptide heterodimer for dual αvβ3 integrin/EGFR-targeted cancer imaging are described. The RGD-GE11 heterodimer was linked with 6-aminohexanoic acid (6-Ahx) and cysteine and conjugated with 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA) to form NOTA-RGD-cys-6-Ahx-GE11. The monomeric peptides, NOTA-cys-6-Ahx-GE11 and c(RGDyK), were formed by a peptide synthesizer. The peptide heterodimer NOTA-RGD-GE11 was obtained by NOTA-cys-6-Ahx-GE11 and maleimidopropyl-c(RGDyK) conjugation with a thioether linkage. The NOTA peptide conjugate was labeled with freshly eluted 68Ga and purified using reversed-phase high-performance liquid chromatography. The 68Ga-NOTA-RGD-cys-6-Ahx-GE11 was successfully prepared, in this study, with a radiochemical yield of 85% and a radiochemical purity of >98%. These results warrant further investigation of this heterodimeric peptide's binding affinity to the receptors. [ABSTRACT FROM AUTHOR]

Purpose: This study employed 3′-deoxy-3′-[F]-fluorothymidine ([F]FLT) microPET scanning to assess the treatment response of histone deacetylase inhibitors (HDACi), e.g., N1-hydroxy-N8-phenyloctanediamide (SAHA) and its iodinated derivative ISAHA, in a hepatoma mouse model. Procedures: The in vitro cytotoxicity of HDACi in various hepatoma cell lines was determined by MTT assay and flow cytometry. ISAHA and SAHA were used to treat HepG2 hepatoma xenograft-bearing mice. The treatment responses were characterized in terms of tumor burden, microPET imaging, and immunohistochemical staining of tumor sections. Results: ISAHA effectively inhibited HepG2 hepatoma cell survival and tumor growth. A significantly reduced tumor uptake during HDACi treatment was noticed in [F]FLT microPET imaging, which was consistent with the findings in immunohistochemical staining. Conclusions: ISAHA can suppress tumor cell proliferation both in vitro and in vivo. [F]FLT PET is a promising modality for evaluating the in vivo therapeutic efficacy of HDACi at the early stage of treatment. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the comparative benefits and limitations of 18F-fluorodeoxyglucose (FDG) PET and CT-MRI in documented or suspected recurrence of cervical cancer after primary treatment. Three patient groups were enrolled. Group A patients had biopsy-documented recurrent or persistent cervical cancer. Group B patients had suspicion of recurrent tumour on CT-MRI without biopsy proof and were potentially curable. Group C patients were in complete remission after previous definitive treatment for histologically confirmed cervical carcinoma but had elevated serum squamous cell carcinoma antigen (tumour marker) levels despite negative CT-MRI. Clinical management decisions were recorded with CT-MRI alone and with additional FDG PET. Discordances and concordances between CT-MRI and FDG PET results were identified and related to final diagnosis as based on histopathology or follow-up. A total of 150 patients (ten regions per patient) were eligible for analysis, with 58 in group A, 52 in group B and 40 in group C. For the 149 discordant regions, 126 (84.6%) had final diagnoses. Of these final diagnoses, there was additional benefit from FDG PET over CT-MRI in 73.8% (93/126), with FDG PET correcting false negatives (FNs) on CT-MRI in 74.2% (69/93) and correcting false positives (FPs) on CT-MRI in 25.8% (24/93). Among lesions confirmed by FDG PET, 75.4% (52/69) were extra-pelvic. There was additional benefit of CT-MRI compared with FDG PET in 26.2% (33/126): in nine (27.3%) CT-MRI results were shown to be true positive (TP) whereas FDG PET yielded FN results, while in 24 (72.7%) CT-MRI corrected FP results on FDG PET. Among the nine FNs on FDG PET that were identified by CT-MRI, four were extra-pelvic. Among the FPs on FDG PET that were excluded by CT-MRI, 79.2% (19/24) were extra-pelvic. For recurrent cervical cancer, the benefits of FDG PET exceed those of CT-MRI owing to the ability of FDG PET to identify extra-pelvic metastases and its higher sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Objective: Previous studies have shown that the accumulation level of FMAU in tumor is proportional to its proliferation rate. This study demonstrated that 2′-deoxy-2′-[18F]fluoro-β-d-arabinofuranosyluracil ([18F]FMAU) is a promising PET probe for noninvasively monitoring the therapeutic efficacy of 6% PEGylated liposomal vinorelbine (lipo-VNB) in a subcutaneous murine NG4TL4 sarcoma mouse model. Methods: Female syngenic FVB/N mice were inoculated with NG4TL4 cells in the right flank. After tumor size reached 150±50mm3 (day 0), lipo-VNB (5mg/kg) was intravenously administered on days 0, 3 and 6. To monitor the therapeutic efficacy of lipo-VNB, [18F]FMAU PET was employed to evaluate the proliferation rate of tumor, and it was compared with that observed from [18F]FDG/[18F]fluoroacetate PET. The expression of proliferating cell nuclear antigen (PCNA) in tumor during treatment was determined by semiquantitative analysis of immunohistochemical staining. Results: A significant inhibition (p<0.001) in tumor growth was observed on day 3 after a single dose treatment. The tumor-to-muscle ratio (T/M) derived from [18F]FMAU-PET images of lipo-VNB-treated group declined from 2.33±0.16 to 1.26±0.03 after three doses of treatment, while that of the control remained steady. The retarded proliferation rate of lipo-VNB-treated sarcoma was confirmed by PCNA immunohistochemistry staining. However, both [18F]FDG and [18F]fluoroacetate microPET imaging did not show significant difference in T/M between the therapeutic and the control groups throughout the entire experimental period. Conclusion: Lipo-VNB can effectively impede the growth of NG4TL4 sarcoma. [18F]FMAU PET is an appropriate modality for early monitoring of the tumor response during the treatment course of lipo-VNB. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: 99mTc-labeled macroaggregated albumin (99mTc-MAA) scintigraphy scan is routinely performed for lung perfusion imaging and for the assessment of in vivo distribution of 90Y-labeled SIR-Spheres prior to selective internal radiation treatment for hepatocellular carcinoma. Positron emission tomography (PET) imaging is superior to gamma scintigraphy in terms of sensitivity, spatial resolution and accuracy of quantification. This study reported that 18 F-labeled macroaggregated albumin (18 F-MAA) is an ideal PET imaging surrogate for 99mTc-MAA. Methods: 18 F-MAA was prepared from the commercial MAA kit via a one-step conjugation with N-succinimidyl 4-18 F-fluorobenzoate (18 F-SFB). The biodistribution study and microPET/microSPECT imaging were conducted in normal SD rats after intravenous injection of 18 F-MAA/99mTc-MAA. A comparison study of these two radiotracers was performed after co-injection via the intrahepatic arterial in a N1S1 hepatoma-bearing SD rat model. Results: The optimal condition for 18 F-MAA preparation is coupling MAA (0.5mg) with 18 F-SFB at 45°C for 5min in a phosphate buffer of pH 8.5. 18 F-MAA was prepared in 60min with high radiochemical yield (30%–35%) and high radiochemical purity (>95%). The in vivo distribution of 18 F-MAA after intravenous injection meets the specifications of MAA depicted in European Pharmacopeia. Our study demonstrated excellent correlation between 18 F-MAA and 99mTc-MAA in the regional distribution of tumor, liver and lungs (R2 =0.965, 0.886 and 0.991, respectively), and also in the tumor-to-liver and tumor-to-lungs ratio (R2 =0.965 and 0.987, respectively) in a N1S1 hepatoma-bearing SD rat model. The organ uptakes derived from animal PET/CT and SPECT/CT imaging after administration of these two tracers were in accordance with those obtained in the distribution studies. Conclusions: Starting from commercial MAA kit, an efficient preparation of 18 F-MAA was successfully established. Highly correlated, almost parallel, regional distribution of 18 F-MAA and 99mTc-MAA in both normal rats and hepatoma-bearing rats was observed. The findings, taken together, demonstrate that 18 F-MAA is an ideal surrogate for 99mTc-MAA for clinical PET applications. [Copyright &y& Elsevier]

Abstract: [18F]Flurobutyl ethacrynic amide ([18F]FBuEA) was prepared from the precursor tosylate N-Boc-N-[4-(toluenesulfonyloxy)butyl]ethacrynic amide with a radiochemical yield of 3%, a specific activity of 48GBq/μmol and radiochemical purity of 98%. Chemical conjugation of [18F]FBuEA with glutathione (GSH) via a self-coupling reaction and enzymatic conjugation under catalysis of glutathiontransferase alpha (GST-α) and π provided about 41% yields of radiochemical conjugated product [18F]FBuEA–GSH, 85% and 5–16%, respectively. The catalytic selectivity of this tracer toward GST-alpha was addressed. Positron emission tomography (PET) imaging of [18F]FBuEA in normal rats showed that a homogeneous pattern of radioactivity was distributed in the liver, suggesting a catalytic role of GST. By contrast, PET images of [18F]FBuEA in rats with thioacetamide-induced cholangiocarcinoma displayed a heterogeneous pattern of radioactive accumulation with cold spots in tumor lesions. PET imaging with [18F]FBuEA could be used for early diagnosis of hepatic tumor with a low GST activity as well as liver function. [Copyright &y& Elsevier]

Abstract: Introduction: Hepatocellular carcinoma is the most common form of primary hepatic carcinoma. A new N2S2 tetradentate ligand, N-[2-(triphenylmethyl)thioethyl]-3-aza-19-ethyloxycarbonyl-3-[2-(triphenylmethyl)thioethyl]octadecanoate (H3MN-16ET), was introduced and labeled with 188Re to create 188Re-MN-16ET in the Lipiodol phase. The potential of 188Re-MN-16ET/Lipiodol for hepatoma therapy was evaluated in a hepatocellular carcinoma animal model of Sprague–Dawley rats implanted with the N1S1 cell line. Methods: Synthesis of H3MN-16ET was described, and characterization was identified by infrared, nuclear magnetic resonance and mass spectra. We compared the effects of transchelating agents (glucoheptonate or tartaric acid) and a reducing agent (stannous chloride) on the complexing of 188Re-perrhenate and H3MN-16ET. Twenty-four rats implanted with hepatoma were injected with 3.7 MBq/0.1 ml of 188Re-MN-16ET/Lipiodol or 188Re-MN-16ET via transcatheter arterial embolization. Biodistribution experiments and single-photon emission computed tomography imaging were performed to investigate tumor accumulation. Results: H3MN-16ET was proved to easily conjugate with the Re isotope and showed good solubility in Lipiodol. The radiochemical purity of 188Re-MN-16ET/Lipiodol with 10 mg tartaric acid and stannous chloride was shown to be more than 90%. The major distribution sites of 188Re-MN-16ET in Sprague–Dawley rats were hepatoma and the liver. However, the radioactivity at the tumor site postadministered with 188Re-MN-16ET was quickly decreased from 9.15±0.23 (at 1 h) to 2.71%±0.18% of injected dose/g (at 48 h). The biodistribution and micro-single-photon emission computed tomography/computed tomography image data showed that 188Re-MN-16ET/Lipiodol was selectively retained at the tumor site, with 11.55±1.44, 13.16±1.46 and 10.67%±0.95% of injected dose/g at 1, 24 and 48 h postinjection, respectively. The radioactivity in normal liver tissue was high but significantly lower than that of the tumors. Conclusion: H3MN-16ET is a suitable tetradentate ligand for 188Re labeling. From the animal data, we suggest that 188Re-MN-16ET/Lipiodol has the potential to be a therapeutic radiopharmaceutical for hepatoma treatment. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 2-Deoxy-2-[18F]fluoro-d-glucose ([18F]FDG), [18F]fluoroacetate ([18F]FAc) and [18F]fluoromisonidazole ([18F]FMISO) were all considered to be positron emission tomography (PET) probes for tumor diagnosis, though based on different rationale of tissue uptake. This study compared the biodistribution, pharmacokinetics and imaging of these three tracers in a sarcoma- and inflammation-bearing mouse model. Methods: C3H mice were inoculated with 2×105 KHT sarcoma cells in the right thigh on Day 0. Turpentine oil (0.1 ml) was injected in the left thigh on Day 11 to induce inflammatory lesion. Biodistribution, pharmacokinetics and microPET imaging of [18F]FMISO, [18F]FDG and [18F]FAc were performed on Day 14 after tumor inoculation. Results: The inflammatory lesions were clearly visualized by [18F]FDG/microPET and autoradiography at 3 days after turpentine oil injection. The tumor-to-muscle and inflammatory lesion-to-muscle ratios derived from microPET imaging were 6.79 and 1.48 for [18F]FMISO, 8.12 and 4.69 for [18F]FDG and 3.72 and 3.19 for [18F]FAc at 4 h post injection, respectively. Among these, the tumor-to-inflammation ratio was the highest (4.57) for [18F]FMISO compared with that of [18F]FDG (1.73) and [18F]FAc (1.17), whereas [18F]FAc has the highest bioavailability (area under concentration of radiotracer vs. time curve, 116.2 h×percentage of injected dose per gram of tissue). Conclusions: MicroPET images and biodistribution studies showed that the accumulation of [18F]FMISO in the tumor is significantly higher than that in inflammatory lesion at 4 h post injection. [18F]FDG and [18F]FAc delineated both tumor and inflammatory lesions. Our results demonstrated the potential of [18F]FMISO/PET in distinguishing tumor from inflammatory lesion. [Copyright &y& Elsevier]