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.     

64Cu-Labeled tetraiodothyroacetic acid-conjugated liposomes for PET imaging of tumor angiogenesis

IntroductionWe synthesized and evaluated ⁶⁴Cu-labeled tetraiodothyroacetic acid (tetrac)-conjugated liposomes for PET imaging of tumor angiogenesis, because tetrac inhibits angiogenesis via integrin α_Vβ₃.MethodsTetrac-PEG-DSPE and DOTA-PEG-DSPE were synthesized and formulated with other lipids into liposomes. The resulting tetrac/DOTA-liposomes were labeled with ⁶⁴Cu at 40 °C for 1 h and purified using a PD-10 column. ⁶⁴Cu-DOTA-liposomes were also prepared for comparison. Human aortic endothelial cell (HAEC) binding studies were performed by incubating the liposomes with the cells at 37 °C. MicroPET imaging followed by tissue distribution study was carried out using U87MG tumor-bearing mice injected with tetrac/⁶⁴Cu-DOTA-liposomes or ⁶⁴Cu-DOTA-liposomes.ResultsHAEC binding studies exhibited that tetrac/⁶⁴Cu-DOTA-liposomes were avidly taken up by the cells from 1.02 %ID at 1 h to 11.89 %ID at 24 h, while ⁶⁴Cu-DOTA-liposomes had low uptake from 0.47 %ID at 1 h to 1.57 %ID at 24 h. MicroPET imaging of mice injected with tetrac/⁶⁴Cu-DOTA-liposomes showed high radioactivity accumulation in the liver and spleen. ROI analysis of the tumor images revealed 1.93 ± 0.12 %ID/g at 1 h and 2.70 ± 0.36 %ID/g at 22 h. In contrast, tumor ROI analysis of ⁶⁴Cu-DOTA-liposomes revealed 0.54 ± 0.08 %ID/g at 1 h and 0.52 ± 0.09 %ID/g at 22 h. Tissue distribution studies confirmed that the tumor uptakes of tetrac/⁶⁴Cu-DOTA-liposomes and ⁶⁴Cu-DOTA-liposomes were 1.75 ± 0.03 %ID/g and 0.36 ± 0.01 %ID/g at 22 h, respectively.ConclusionThese results demonstrate that tetrac/⁶⁴Cu-DOTA-liposomes have significantly enhanced tumor uptake compared to ⁶⁴Cu-DOTA-liposomes due to tetrac conjugation. Further studies are warranted to reduce the liver and spleen uptake of tetrac/⁶⁴Cu-DOTA-liposomes.     

First 18F-labeled ligand for PET imaging of uPAR: In vivo studies in human prostate cancer xenografts

Urokinase-type plasminogen activator receptor (uPAR) is overexpressed in human prostate cancer and uPAR has been found to be associated with metastatic disease and poor prognosis. AE105 is a small linear peptide with high binding affinity to uPAR. We synthesized an N-terminal NOTA-conjugated version (NOTA-AE105) for development of the first ¹⁸F-labeled uPAR positron-emission-tomography PET ligand using the Al¹⁸F radiolabeling method. In this study, the potential of ¹⁸F-AlF-NOTA-AE105 to specifically target uPAR-positive prostate tumors was investigated.MethodsNOTA-conjugated AE105 was synthesized and radiolabeled with ¹⁸F-AlF according to a recently published optimized protocol. The labeled product was purified by reverse phase high performance liquid chromatography RP-HPLC. The tumor targeting properties were evaluated in mice with subcutaneously inoculated PC-3 xenografts using small animal PET and ex vivo biodistribution studies. uPAR-binding specificity was studied by coinjection of an excess of a uPAR antagonist peptide AE105 analogue (AE152).ResultsNOTA-AE105 was labeled with ¹⁸F-AlF in high radiochemical purity (> 92%) and yield (92.7%) and resulted in a specific activity of greater than 20 GBq/μmol. A high and specific tumor uptake was found. At 1 h post injection, the uptake of ¹⁸F-AlF-NOTA-AE105 in PC-3 tumors was 4.22 ± 0.13%ID/g. uPAR-binding specificity was demonstrated by a reduced uptake of ¹⁸F-AlF-NOTA-AE105 after coinjection of a blocking dose of uPAR antagonist at all three time points investigated. Good tumor-to-background ratio was observed with small animal PET and confirmed in the biodistribution analysis. Ex vivo uPAR expression analysis on extracted tumors confirmed human uPAR expression that correlated close with tumor uptake of ¹⁸F-AlF-NOTA-AE105.ConclusionThe first ¹⁸F-labeled uPAR PET ligand, ¹⁸F-AlF-NOTA-AE105, has successfully been prepared and effectively visualized noninvasively uPAR positive prostate cancer. The favorable in vivo kinetics and easy production method facilitate its future clinical translation for identification of prostate cancer patients with an invasive phenotype and poor prognosis.     

Evaluation of 18F-labeled BODIPY dye as potential PET agents for myocardial perfusion imaging

IntroductionDespite the great potential of positron emission tomography/computed tomography (PET/CT) in cardiovascular disease imaging, one of the major limitations is the availability of PET probes with desirable half-lives and reasonable cost. In this report, we hypothesized that lipophilic cationic BODIPY dye could be selectively accumulated in cardiac muscle, possibly for the development of novel PET myocardial perfusion imaging (MPI) probes.MethodsA ¹⁸F-labeled BODIPY dye ([¹⁸F]1) was synthesized efficiently through a fluoride exchange reaction catalyzed by the Lewis acid tin chloride (SnCl₄). The compound was first evaluated by a cellular uptake assay in vitro, followed by biodistribution and microPET imaging studies in vivo.Results[¹⁸F]1 was obtained in more than 90% labeling yield, with > 98% radiochemical purity. The HEK-293 cellular uptake assay showed that the preferential uptake of [¹⁸F]1 could be related to the cell membrane potential. The biodistribution data demonstrated high levels of [¹⁸F]1 accumulation in the heart. In the biodistribution study in mice, the radioactivity uptake in the heart, blood, liver and lung was 3.01 ± 0.44, 0.39 ± 0.09, 0.69 ± 0.07, 1.71 ± 0.27%ID/g, respectively, at 3 h post-injection (p.i.). The heart-to-lung and heart-to-liver ratios are 1.76 ± 0.14 and 4.37 ± 0.51 at 3 h p.i., respectively. Volume-of-interest analysis of the microPET images correlated well with the biodistribution studies in mice. The heart was clearly visualized in normal rats, with 0.72 ± 0.18, 0.69 ± 0.18, 0.67 ± 0.20 and 0.59 ± 0.17%ID/g uptake at 0.5, 1, 2 and 4 h p.i., respectively.Conclusions¹⁸F-labeled BODIPY dye showed good heart uptake and heart-to-blood and heart-to-lung contrast. A ¹⁸F-labeled BODIPY dyes may represent a new category of cationic PET agents for myocardial perfusion imaging.     

Synthesis and in vivo preclinical evaluation of an 18F labeled uPA inhibitor as a potential PET imaging agent

IntroductionThe urokinase plasminogen activator (uPA) system is a proteolytic cascade involved in tumor invasion and metastasis. uPA and its inhibitor PAI-1 are described as biomarkers for breast cancer with the highest level of evidence. The present study describes the synthesis and first in vivo application of an activity based uPA PET probe.MethodsBased on the design of a small irreversible and selective uPA inhibitor we developed an ¹⁸F-labeled activity based probe for uPA imaging. Human uPA expressing MDA-MB-231-luc2-GFP cells were inoculated in the mammary fat pads of nude mice and treated with the probe once tumors reached a volume of 150 mm³. Scans were performed at 0.25, 0.75, 1.5, 4 and 6 h post injection. To evaluate tumor uptake in vivo and ex vivo data were gathered. Biodistribution data of the organs and tissues of interest were collected at all time points. Due to a relatively low tumor uptake, probe stability was further evaluated.ResultsThe uPA targeting PET tracer was produced in high purity and with good specific radioactivity. In vivo PET data showed a maximum tumor uptake of 2,51 ± 0,32 %ID/g at 4 h p.i. A significant correlation between in vivo and ex vivo tumor uptake calculation was found (R = 0.75; p < 0.01). Due to a high blood signal at all time points, probe stability was further examined revealing high plasma protein binding and low plasma stability.ConclusionsIn vivo and ex vivo results clearly demonstrate that uPA expressing tumors can be detected with non-invasive PET imaging. Stability tests suggest that further optimization is needed to provide a better tumor-to-background contrast.     

Differentiation and diagnosis of benign and malignant testicular lesions using 18F-FDG PET/CT

ObjectivesThe purpose of this study was to evaluate the differential diagnostic value of ¹⁸F-fluorodeoxy glucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) for benign and malignant testicular lesions.MethodsThe PET/CT scans of 53 patients with testicular lesions confirmed by biopsy or surgical pathology were retrospectively analyzed. There were 32 cases of malignant tumors and 21 cases of benign lesions. Differences in the maximum standardized uptake value (SUVmax) measurements and the SUVmax lesion/background ratios between benign and malignant lesions were analyzed. The diagnostic value of this PET/CT modality for the differential diagnosis of benign versus malignant testicular lesions was calculated.ResultsThe differences in the SUVmax measurements and the SUVmax lesion/background ratios between benign and malignant lesions were statistically significant (SUVmax: Z = −4.295, p = 0.000; SUVmax lesion/background ratio: Z = −5.219, p = 0.000); specifically, both of these indicators were higher in malignant lesions compared to benign lesions. An SUVmax of 3.75 was the optimal cutoff value to differentiate between benign and malignant testicular lesions. The diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of this PET/CT modality in the differential diagnosis of benign versus malignant testicular lesions were 90.6%, 80.9%, 86.8%, 87.9%, and 85.0%, respectively.Conclusions¹⁸F-FDG PET/CT can accurately identify benign and malignant testicular lesions.     

Preliminary evaluation of 1′-[18F]fluoroethyl-β-D-lactose ([18F]FEL) for detection of pancreatic cancer in nude mouse orthotopic xenografts

IntroductionEarly detection of pancreatic cancer could save many thousands of lives. Non-invasive diagnostic imaging, including PET with [¹⁸F]FDG, has inadequate resolution for detection of small (2–3 mm) pancreatic tumours. We demonstrated the efficacy of PET imaging with an ¹⁸F-labelled lactose derivative, [¹⁸F]FEDL, that targets HIP/PAP, a biomarker that is overexpressed in the peritumoural pancreas. We developed another analogue, 1-[¹⁸F]fluoroethyl lactose ([¹⁸F]FEL), which is simpler to synthesise, for the same application. We conducted a preliminary evaluation of the new probe and its efficacy in detecting orthotopic pancreatic carcinoma xenografts in mice.MethodsXenografts were developed in nude mice by injecting L3.6pl/GL⁺ pancreatic carcinoma cells into the pancreas of each mouse. Tumour growth was monitored by bioluminescence imaging (BLI); accuracy of BLI tumour size estimates was verified by MRI in two representative mice. When the tumour size reached approximately 2–3 mm, the animals were injected with [¹⁸F]FEL (3.7 MBq) and underwent static PET/CT scans. Blood samples were collected at 2, 5, 10, 20 and 60 min after [¹⁸F]FEL injection to track blood clearance. Following imaging, animals were sacrificed and their organs and tumours/pancreatic tissue were collected and counted on a gamma counter. Pancreas, including tumour, was frozen, sliced and used for autoradiography and immunohistochemical analysis of HIP/PAP expression.ResultsTumour growth was rapid, as observed by BLI and MRI. Blood clearance of [¹⁸F]FEL was bi-exponential, with half-lives of approximately 3.5 min and 40 min. Mean accumulation of [¹⁸F]FEL in the peritumoural pancreatic tissue was 1.29 ± 0.295 %ID/g, and that in the normal pancreas of control animals was 0.090 ± 0.101 %ID/g. [¹⁸F]FEL was cleared predominantly by the kidneys. Comparative analysis of autoradiographic images and immunostaining results demonstrated a correlation between [¹⁸F]FEL binding and HIP/PAP expression.Conclusion[¹⁸F]FEL may be useful for non-invasive imaging of early-stage pancreatic tumours by PET. The results warrant further studies.     

Synthesis and radiopharmacological evaluation of a high-affinity and metabolically stabilized 18F-labeled bombesin analogue for molecular imaging of gastrin-releasing peptide receptor-expressing prostate cancer

IntroductionBombesin (BBN) and BBN analogues have attracted much attention as high-affinity ligands for selective targeting of the gastrin-releasing peptide (GRP) receptor. GRP receptors are overexpressed in a variety of human cancers including prostate cancer. Radiolabeled BBN derivatives are promising diagnostic probes for molecular imaging of GRP receptor-expressing prostate cancer. This study describes the synthesis and radiopharmacological evaluation of various metabolically stabilized fluorobenzoylated bombesin analogues (BBN-1, BBN-2, BBN-3).MethodsThree fluorobenzoylated BBN analogues containing an aminovaleric (BBN-1, BBN-2), or an aminooctanoic acid linker (BBN-3) were tested in a competitive binding assay against ¹²⁵I-[Tyr⁴]-BBN for their binding potency to the GRP receptor. Intracellular calcium release in human prostate cancer cells (PC3) was measured to determine agonistic or antagonistic profiles of fluorobenzoylated BBN derivatives. Bombesin derivative BBN-2 displayed the highest inhibitory potency toward GRP receptor (IC₅₀ = 8.7 ± 2.2 nM) and was subsequently selected for radiolabeling with fluorine-18 (¹⁸F) through acylation with N-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB). The radiopharmacological profile of ¹⁸F-labeled bombesin [¹⁸F]BBN-2 was evaluated in PC3 tumor-bearing NMRI nude mice involving metabolic stability studies, biodistribution experiments and dynamic small-animal PET studies.ResultsAll fluorobenzoylated BBN derivatives displayed high inhibitory potency toward the GRP receptor (IC₅₀ = 8.7–16.7 nM), and all compounds exhibited antagonistic profiles as determined in an intracellular calcium release assay. The ¹⁸F-labeled BBN analogue [¹⁸F]BBN-2 was obtained in 30% decay-corrected radiochemical yield with high radiochemical purity > 95% after semi-preparative HPLC purification. [¹⁸F]BBN-2 showed high metabolic stability in vivo with 65% of the radiolabeled peptide remaining intact after 60 min p.i. in mouse plasma. Biodistribution experiments and dynamic small-animal PET studies demonstrated high tumor uptake of [¹⁸F]BBN-2 in PC3 xenografts (2.75 ± 1.82 %ID/g after 5 min and 2.45 ± 1.25 %ID/g after 60 min p.i.). Specificity of radiotracer uptake in PC3 tumors was confirmed by blocking experiments.ConclusionThe present study demonstrates that ¹⁸F-labeled BBN analogue [¹⁸F]BBN-2 is a suitable PET radiotracer with favorable metabolic stability in vivo for molecular imaging of GRP receptor-positive prostate cancer.     

Whole-body 18F-FDG PET/CT for M staging in the patient with newly diagnosed nasopharyngeal carcinoma: Who needs?

ObjectiveAlthough whole-body fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) (¹⁸F-FDG PET/CT) is commonly used for M staging of newly diagnosed nasopharyngeal carcinoma (NPC), some patients may not benefit from this procedure. The present study investigated which patients require this modality for M staging.MethodsWhole-body ¹⁸F FDG PET/CT results and clinical data were collected for 264 patients with newly diagnosed NPC. The relationships between distant metastasis and age, gender, pathological type, lesion size, SUVmax-T, T staging, N staging, SUVmax-N and Epstein-Barr virus (EBV) quantity were retrospectively analysed to identify factors associated with increased risk.ResultsOf the 264 patients, only 37 (14.0%) were diagnosed with distant metastasis. Using multiple logistic regression analysis, EBV-positivity (OR = 13.1; 95% CI:1.61,106.80), N staging (OR = 3.05; 95% CI:1.41,6.63) and T staging (OR = 2.16; 95% CI:1.10, 4.24) were significantly related to distant metastasis (all P < 0.05). EBV DNA levels ≥ 9000 copies/ml, N3 stage and T4 stage were identified as high risk factors. A low risk of distant metastasis was found in patients with 0–1 risk factors and in those with 2 specific risk factors, T3/T4 and N2/N3 staging. Patients with EBV DNA levels ≥9000 copies/ml and N3 or T4 staging and those with 3 risk factors had a medium or high risk, with a much higher incidence of distant metastasis (χ² = 29.896, P = 0.000), and needed a whole-body ¹⁸F FDG PET/CT for M staging.ConclusionsDue to the low incidence of distant metastasis, only patients with medium or high risk need to undergo a whole-body scan.     

18F-FDG PET/CT and contrast-enhanced CT findings of pulmonary cryptococcosis

PurposePulmonary cryptococcosis is an uncommon cause of pulmonary nodules in non-AIDS patients. This study reports the ¹⁸F-fluorodeoxyglucose-positron emission tomography (¹⁸F-FDG PET/CT) and contrast-enhanced CT (CE-CT) findings of 42 patients with pulmonary cryptococcosis.Materials and methodsA retrospective review of the ¹⁸F-FDG PET/CT and CE-CT findings of 42 patients with histologically proven pulmonary cryptococcosis was conducted. All patients underwent PET/CT and CE-CT in the same session. The CT diagnosis was based on the location, morphological features, and enhancement of lesions. The PET/CT findings were recorded, and clinical data and surgical and histopathological findings were collected.ResultsThe results of the PET scans revealed that 37 (88%) of 42 patients showed higher FDG uptake, and 5 (12%) patients demonstrated lower FDG uptake than the mediastinal blood pool. The maximum standardized uptake value (SUV) of pulmonary cryptococcosis ranged from 1.4 to 13.0 (average: 5.7 ± 3.3, median 4.9). A single nodular pattern was the most prevalent pattern observed and was found in 29 (69%) patients. This pattern was followed by scattered nodular (n = 4, 10%), clustered nodular (n = 3, 7%), mass-like (n = 3, 7%), and bronchopneumonic (n = 3, 7%) patterns. The most frequent pattern of immunocompetent patients was the single nodular pattern (29 of 33, 88%). Immunocompromised patients most frequently pattern exhibited mass-like (3 of 9, 33%) and bronchopneumonic (3 of 9, 33%) patterns.ConclusionPulmonary cryptococcosis most commonly appears as single nodules in immunocompetent patients. Mass-like and bronchopneumonic patterns were common in immunocompromised patients. In 88% of patients, lung lesions showed high FDG uptake, thus mimicking a possible malignant condition.     

Simultaneous whole-body 18F-FDG PET-MRI in primary staging of breast cancer: A pilot study

PurposeAccurate initial staging in breast carcinoma is important for treatment planning and for establishing the likely prognosis. The purpose of this study was to assess the utility of whole body simultaneous ¹⁸F-FDG PET-MRI in initial staging of breast carcinoma.Methods36 patients with histologically confirmed invasive ductal carcinoma underwent simultaneous whole body ¹⁸F-FDG PET-MRI on integrated 3 T PET-MR scanner (Siemens Biograph mMR) for primary staging. Primary lesion, nodes and metastases were evaluated on PET, MRI and PET-MRI for lesion count and diagnostic confidence (DC). Kappa co relation analysis was done to assess agreement between the satellite, nodal and metastatic lesions detected by PET and MRI. Histopathology, clinical/imaging follow-up served as the reference standard.Results36 patients with 37 histopathologically proven index breast cancer were retrospectively studied. Of 36 patients, 25 patients underwent surgery and 11 patients received systemic therapy. All index cancers were seen on PET and MR. Fused PET-MRI showed highest diagnostic confidence score of 5 as compared to PET (median 4; range 3–5) and MRI (median 4; range 4–5) alone. 2/36 (5.5%) patients were detected to have unsuspected contralateral synchronous cancer. 47 satellite lesions were detected on DCE MRI of which 23 were FDG avid with multifocality and multicentricity in 21 (58%) patients. Kappa co relation analysis revealed fair agreement for satellite lesion detection by the two modalities (κ = 0.303; P = 0.003).The study showed a sensitivity of 60% and 93.3% on PET and MRI respectively for detection of axillary lymph nodes with a specificity of 91% for both and a false negative rate of 6.7% on MRI and 40% on PET. Kappa co relation analysis between PET and MRI for all the lymph nodes detected revealed fair agreement by the two modalities (κ = 0.337; P = 0.000). Combined PET-MRI increased diagnostic confidence for nodal involvement (median DC 5, range 4–5; P < 0.05).Distant metastases were found in 8/36 (22%) patients at the time of diagnosis with a total of 91 metastatic lesions on PET (DC ≥ 4) and 105 on MRI (DC ≥ 4), the difference being statistically significant (P = 0.001) while Kappa co relation analysis showed significant agreement between the two modalities (κ = 0.667; P = 0.000). Overall PET-MRI led to a change in management in 12 (33.3%) patients.ConclusionIn this pilot study, simultaneous ¹⁸F-FDG PET-MR, has been found to be useful in whole-body initial staging of breast cancer patients.     

68Ga-NODAGA-VEGF121 for in vivo imaging of VEGF receptor expression

PurposeVascular endothelial growth factor (VEGF) is a crucial regulator of angiogenesis. In this study, we labeled VEGF₁₂₁ with ⁶⁸Ga using a hydrophilic chelating agent, NODAGA and evaluated the resulting ⁶⁸Ga-NODAGA-VEGF₁₂₁ for in vivo imaging of VEGF receptor (VEGFR) expression.MethodsNODAGA-VEGF₁₂₁ was prepared and its binding affinity for VEGFR2 was measured using ¹²⁵I-VEGF₁₂₁. ⁶⁸Ga-NODAGA-VEGF₁₂₁ was prepared by labeling NODAGA-VEGF₁₂₁ with ⁶⁸GaCl₃ followed by purification using a PD-10 column. Human aortic endothelial cell (HAEC) binding studies of ⁶⁸Ga-NODAGA-VEGF₁₂₁ were performed at 37 °C for 4 h. MicroPET imaging followed by biodistribution studies were performed in U87MG tumor-bearing mice injected with ⁶⁸Ga-NODAGA-VEGF₁₂₁. Immunofluorescence staining of the tumor tissues was performed to verify VEGFR2 expression.ResultsBinding affinity of NODAGA-VEGF₁₂₁ for VEGFR2 was found to be comparable to that of VEGF₁₂₁. ⁶⁸Ga-NODAGA-VEGF₁₂₁ was prepared in 47.8% yield with specific activity of 3.4 GBq/mg. ⁶⁸Ga-NODAGA-VEGF₁₂₁ was avidly taken up by HAECs with a time-dependent increase from 9.88 %ID at 1 h to 20.86 %ID at 4 h. MicroPET imaging of mice demonstrated high liver and spleen uptake with clear visualization of tumor at 1 h after injection. ROI analysis of tumors revealed 2.53 ± 0.11 %ID/g at 4 h after injection. In the blocking study, tumor uptake was inhibited by 29% at 4 h. Subsequent biodistribution studies demonstrated tumor uptake of 2.38 ± 0.15 %ID/g. Immunofluorescence staining of the tumor tissues displayed high level of VEGFR2 expression.ConclusionsThese results demonstrate that ⁶⁸Ga-NODAGA-VEGF₁₂₁ led to VEGFR-specific distribution in U87MG tumor-bearing mice. This study also suggests that altered physicochemical properties of VEGF₁₂₁ after radiolabeling may affect biodistribution of the radiolabeled VEGF₁₂₁.     

Association of pharmacokinetic and metabolic parameters derived using simultaneous PET/MRI: Initial findings and impact on response evaluation in breast cancer

PurposeTo study relationships among pharmacokinetic and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET parameters obtained through simultaneous PET/MRI in breast cancer patients and evaluate their combined potential for response evaluation.MethodsThe study included 41 breast cancer patients for correlation study and 9 patients (pre and post therapy) for response evaluation. All patients underwent simultaneous PET/MRI with dedicated breast imaging. Pharmacokinetic parameters and PET parameters for tumor were derived using an in- house developed and vendor provided softwares respectively. Relationships between SUV and pharmacokinetic parameters and clinical as well as histopathologic parameters were evaluated using Spearman correlation analysis. Response to chemotherapy was derived as percentage reduction in size and in parameters post therapy.ResultsSignificant correlations were observed between SUVmean, max, peak, TLG with K^trans (ρ = 0.446, 0.417, 0.491, 0.430; p ≤ 0.01); with Kep(ρ = 0.303, ρ = 0.315, ρ = 0.319; p ≤ 0.05); and with iAUC(ρ = 0.401, ρ = 0.410, ρ = 0.379; p ≤ 0.05, p ≤ 0.01). The ratio of ve/iAUC showed significant negative correlation to SUVmean, max, peak and TLG (ρ = 0.420, 0.446, 0.443, 0.426; p ≤ 0.01). Ability of SUV as well as pharmacokinetic parameters to predict response to therapy matched the RECIST criteria in 9 out of 11 lesions in 9 patients. Maximum post therapy quantitative reduction was observed in SUVpeak, TLG and K^trans.ConclusionSimultaneous PET/MRI enables illustration of close interactions between glucose metabolism and pharmacokinetic parameters in breast cancer patients and potential of their simultaneity in response assessment to therapy.     

Impact of blood glucose,diabetes, insulin,and obesity on standardized uptake values in tumors and healthy organs on 18F-FDG PET/CT

IntroductionChronically altered glucose metabolism interferes with ¹⁸F-FDG uptake in malignant tissue and healthy organs and may therefore lower tumor detection in ¹⁸F-FDG PET/CT. The present study assesses the impact of elevated blood glucose levels (BGL), diabetes, insulin treatment, and obesity on ¹⁸F-FDG uptake in tumors and biodistribution in normal organ tissues.Methods¹⁸F-FDG PET/CT was analyzed in 90 patients with BGL ranging from 50 to 372 mg/dl. Of those, 29 patients were diabetic and 21 patients had received insulin prior to PET/CT; 28 patients were obese with a body mass index > 25. The maximum standardized uptake value (SUV_max) of normal organs and the main tumor site was measured. Differences in SUV_max in patients with and without elevated BGLs, diabetes, insulin treatment, and obesity were compared and analyzed for statistical significance.ResultsIncreased BGLs were associated with decreased cerebral FDG uptake and increased uptake in skeletal muscle. Diabetes and insulin diminished this effect, whereas obesity slightly enhanced the outcome. Diabetes and insulin also increased the average SUV_max in muscle cells and fat, whereas the mean cerebral SUV_max was reduced. Obesity decreased tracer uptake in several healthy organs by up to 30%. Tumoral uptake was not significantly influenced by BGL, diabetes, insulin, or obesity.ConclusionsChanges in BGLs, diabetes, insulin, and obesity affect the FDG biodistribution in muscular tissue and the brain. Although tumoral uptake is not significantly impaired, these findings may influence the tumor detection rate and are therefore essential for diagnosis and follow-up of malignant diseases.     

Prognostic value of pretreatment volume-based quantitative 18F-FDG PET/CT parameters in patients with malignant pleural mesothelioma

PurposeTo investigate the relationships between pretreatment volume-based quantitative ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) parameters and overall survival (OS) in patients with malignant pleural mesothelioma (MPM).Materials and methodsWe retrospectively reviewed data from 201 MPM patients, of whom 38 underwent surgical resection, and calculated the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), including primary tumors and nodal or distant metastatic lesions, on pretreatment ¹⁸F-FDG PET/CT. Relationships between clinicopathological factors (age, sex, performance status, European Organization for Research and Treatment of Cancer [EORTC] score, histological subtype, TNM stage, and treatment strategy), volume-based quantitative PET/CT parameters, and OS were evaluated using a Cox proportional hazards model and log-rank test.ResultsThe median follow-up was 15 months (range, 1–96 months; median, 17 months). In a univariate analysis of all patients, older age (p < 0.05), high EORTC score (p < 0.001), non-epithelioid histological subtype (p < 0.001), high T stage (p < 0.001), positive N/M status (p < 0.05, p < 0.001), advanced TNM stage (p < 0.001), non-surgical treatment (p < 0.001), and high SUVmax (p < 0.001), MTV (p < 0.001), or TLG (p < 0.001) were associated with significantly shorter OS. A multivariate analysis confirmed non-epithelioid subtype (hazard ratio [HR]: 1.69, 95% confidence interval [CI]: 1.14–2.48; p < 0.05), non-surgical treatment (HR: 0.58, 95% CI: 0.34–0.95; p < 0.05), and high TLG (HR: 1.97, 95% CI: 1.14–3.44; p < 0.05) as independent negative predictors.ConclusionsPretreatment volume-based quantitative ¹⁸F-FDG PET/CT parameters, especially TLG, could serve as potential surrogate markers for MPM prognosis.     

Evaluation of 3'-deoxy-3'-18F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice.

3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) has been suggested as a new PET tracer for imaging tumor proliferation. We investigated the use of 18F-FLT to monitor the response of tumors to radiotherapy and photodynamic therapy (PDT) in mice. METHODS: C3H/He mice bearing an SCCVII tumor were treated with single-dose x-ray irradiation of 20 Gy. Tumor uptake was examined for 18F-FLT, 3H-thymidine (3H-Thd), 18F-FDG, and 14C-deoxyglucose (14C-DG) at 6 h, 12 h, 24 h, 3 d, and 7 d after radiotherapy. BALB/c nu/nu mice bearing a HeLa tumor were treated with PDT. Tumor uptake was examined for the 4 tracers at 24 h after PDT. Expression of proliferating cell nuclear antigen (PCNA) was determined in untreated and treated tumors. RESULTS: In the biodistribution study, considerable uptake of 18F-FLT was observed in both tumor types. Tumor volumes decreased to 39.3% +/- 22.4% at 7 d after radiotherapy. The PCNA labeling index was reduced in x-ray-irradiated tumors (control, 53.2% +/- 8.7%; 6 h, 38.5% +/- 5.3%; 24 h after radiotherapy, 36.8% +/- 5.3%). 18F-FLT uptake in tumor expressed as the percentage of the injected dose per gram of tumor (%ID/g) decreased significantly at 6 h and remained low until 3 d after radiotherapy (control, 9.7 +/- 1.2 %ID/g; 6 h, 5.9 +/- 0.4 %ID/g; 24 h, 6.1 +/- 1.3 %ID/g; 3 d after radiotherapy, 6.4 +/- 1.1 %ID/g). 18F-FDG uptake tended to gradually decrease but a significant decrease was found only at 3 d (control, 12.1 +/- 2.7 %ID/g; 6 h, 13.3 +/- 2.3 %ID/g; 24 h, 8.6 +/- 1.8 %ID/g; 3 d after radiotherapy, 6.9 +/- 1.2 %ID/g). PDT resulted in a reduction of the PCNA labeling index (control, 82.0% +/- 8.6%; 24 h after PDT, 13.5% +/- 12.7%). Tumor uptake of 18F-FLT decreased (control, 11.1 +/- 1.3 %ID/g; 24 h after PDT, 4.0 +/- 2.2 %ID/g), whereas 18F-FDG uptake did not decrease significantly after PDT (control, 3.5 +/- 0.6 %ID/g; 24 h after PDT, 2.3 +/- 1.1 %ID/g). Changes in the uptake of 18F-FLT and 18F-FDG were similar to those of 3H-Thd and 14C-DG, respectively. CONCLUSION: In our model system, changes in 18F-FLT uptake after radiotherapy and PDT were correlated with those of 3H-Thd and the PCNA labeling index. The decrease in 18F-FLT uptake after treatments was more rapid or pronounced than that of 18F-FDG. Therefore, 18F-FLT may be a feasible PET tracer for monitoring response to therapy in oncology.     

Quantification accuracy of neuro-oncology PET data as a function of emission scan duration in PET/MR compared to PET/CT

ObjectivesTo evaluate and compare the effect of reduced acquisition time, as a surrogate of injected activity, on the PET quantification accuracy in PET/CT and PET/MR imaging.MethodsTwenty min ¹⁸F-FDG phantom measurements and 10 min ¹⁸F-FET brain scans were acquired in a Biograph-True-Point-True-View PET/CT (n = 8) and a Biograph mMR PET/MR (n = 16). Listmode data were repeatedly split into frames of 1 min to 10 min length and reconstructed using two different reconstruction settings of a 3D-OSEM algorithm: with post-filtering (“OSEM”), and without post-filtering but with resolution recovery (“PSF”). Recovery coefficients (RC_max, RC_A50) and standard uptake values (SUV_max, SUV_A50) were evaluated.ResultsRC_max (phantom) and SUV_max (patients) increased significantly when reducing the frame duration. Significantly lower deviations were observed for RC_A50 and SUV_A50, respectively, making them more appropriate to compare PET studies at different number of counts. No statistical significant differences were observed when using post-filtering and reducing the frame time to 4 min (RC_A50, reference 20 min, phantom) and to 3 min (SUV_A50, reference 10 min, patients).ConclusionsFor hybrid aminoacid brain imaging, frame duration (or injected activity) can potentially be reduced to 30% of the standard used in clinical routine without significant changes on the quantification accuracy of the PET images if adequate reconstruction settings and quantitative measures are used. Frame times below 4 min in the NEMA phantom are not advisable to obtain quantitative and reproducible measures.     

Monitoring tumor response with [18F]FMAU in a sarcoma-bearing mouse model after liposomal vinorelbine treatment

ObjectivePrevious 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.MethodsFemale syngenic FVB/N mice were inoculated with NG4TL4 cells in the right flank. After tumor size reached 150 ± 50 mm³ (day 0), lipo-VNB (5 mg/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.ResultsA 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.ConclusionLipo-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.     

Radiosynthesis,biodistribution and imaging of [11C]YM155, a novel survivin suppressant,in a human prostate tumor-xenograft mouse model

IntroductionSepantronium bromide (YM155) is an antitumor drug in development and is a first-in-class chemical entity, which is a survivin suppressant. We developed a radiosynthesis of [¹¹C]YM155 to non-invasively evaluate its tissue and tumor distribution in mice bearing human prostate tumor xenografts.MethodsMethods utilizing [¹¹C]acetyl chloride and [¹¹C]methyl triflate, both accessible with automated radiosynthesis boxes, were evaluated. The O-methylation of ethanolamine-alkolate with [¹¹C]methyl triflate proved to be the key development toward a rapid and efficient process. The whole-body distribution of [¹¹C]YM155 in PC-3 xenografted mice was examined using a planar positron imaging system (PPIS).ResultsSufficient quantities of radiopharmaceutical grade [¹¹C]YM155 were produced for our PET imaging and distribution studies. The decay corrected (EOB) radiochemical yield was 16–22%, within a synthesis time of 47 min. The radiochemical purity was higher than 99%, and the specific activity was 29–60 GBq/μmol (EOS). High uptake levels of radioactivity (%ID/g, mean ± SE) were observed in tumor (0.0613 ± 0.0056), kidneys (0.0513 ± 0.0092), liver (0.0368 ± 0.0043) and cecum (0.0623 ± 0.0070). The highest tumor uptake was observed at an early time point (from 10 min after) following injection. Tumor-to-blood and tumor-to-muscle uptake ratios of [¹¹C]YM155, at 40 min after injection, were 26.5 (± 2.9) and 25.6 (± 3.6), respectively.ConclusionA rapid method for producing a radiopharmaceutical grade [¹¹C]YM155 was developed. An in vivo distribution study using PPIS showed high uptake of [¹¹C]YM155 in tumor tissue. Our methodology may facilitate the evaluation and prediction of response to YM155, when given as an anti-cancer agent.     

Kit-like 18F-labeling of RGD-19F-Arytrifluroborate in high yield and at extraordinarily high specific activity with preliminary in vivo tumor imaging

IntroductionPositron Emission Tomography (PET) is a rapidly expanding, cutting edge technology for preclinical evaluation, cancer diagnosis and staging, and patient management. A one-step aqueous ¹⁸F-labeling method, which can be applied to peptides to provide functional in vivo images, has been a long-standing challenge in PET imaging. Over the past few years, we have sought a rapid and mild radiolabeling method based on the aqueous radiosynthesis of in vivo stable aryltrifluoroborate (ArBF₃^?) conjugates. Recent access to production levels of ¹⁸F-Fluoride led to a fluorescent-¹⁸F-ArBF₃^? at unprecedentedly high specific activities of 15 Ci/μmol. However, extending this method to labeling peptides as imaging agents has not been explored.MethodsIn order to extend these results to a peptide of clinical interest in the context of production-level radiosynthesis, we applied this new technology for labeling RGD, measured its specific activity by standard curve analysis, and carried out a preliminary evaluation of its imaging properties.ResultsRGD was labeled in excellent radiochemical yields at exceptionally high specific activity (~ 14 Ci/μmol) (n = 3). Preliminary tumor-specific images corroborated by ex vivo biodistribution data with blocking controls show statistically significant albeit relatively low tumor uptake along with reasonably high tumor:blood ratios (n = 3).ConclusionsIsotope exchange on a clinically useful ¹⁸F-ArBF₃^? radiotracer leads to excellent radiochemical yields and exceptionally high specific activities while the anionic nature of the aryltrifluoroborate prosthetic results in very rapid clearance. Since rapid clearance of the radioactive tracer is generally desirable for tracer development, these results suggest new directions for varying linker arm composition to slightly retard clearance rather than enhancing it.Advances in Knowledge and Implications for patient CareThis work is the first to use production levels of ¹⁸F-activity to directly label RGD at specific activities that are an order of magnitude higher than most reports and thereby increases the distribution window for radiotracer production and delivery.