Usefulness of 11C-Choline Positron Emission Tomography for Genital Chlamydial Infection Assessment in a Balb/c Murine Model

Purpose

The aim of this study is to explore the feasibility of ¹¹C-Choline PET in the assessment of the degree of inflammation in the Chlamydia muridarum genital infection model.

Procedures

Forty female Balb/c mice received 2.5 mg of medroxyprogesterone acetate i.m. 9 and 2 days prior to the infection: 21 mice were infected by C. muridarum into the vaginal vault, 12 mice were treated with inactivated chlamydiae, and 7 mice were SPG buffer-treated as negative controls. Three healthy control mice were not treated with progesterone. Mice in each category were randomly subdivided in two groups: (1) sacrificed at 5, 10, 15, and 20 days for histological analysis and (2) undergoing ¹¹C-Choline PET at days 5, 10, and 20 post-infection (20 MBq of ¹¹C-Choline, uptake time of 10 min, acquisition through a small-animal PET tomograph for 15 min).

Results

Infected animals showed a significantly higher standardized uptake value than both controls and animals inoculated with heat-inactivated chlamydiae in each PET scan (P?<?0.05). All organs of the infected animals had scores of inflammation ranging between 2 and 3 at day 5, decreasing to 1–2 at day 20.

Conclusions

This preliminary result demonstrated that ¹¹C-Choline PET can highlight a specific proliferation mechanism of inflammatory cells induced by C. muridarum, thanks to a very high sensitivity in detecting very small amounts of tracer in inflammatory cells.     

Differentiation of Reactive and Tumor Metastatic Lymph Nodes with Diffusion-weighted and SPIO-Enhanced MRI

Objectives

Determination of lymphatic metastasis is of great importance for both treatment planning and patient prognosis. We aim to distinguish tumor metastatic lymph nodes (TLNs) and reactive lymph nodes (RLNs) with diffusion-weighted and superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI).

Materials and Methods

Ipsilateral popliteal lymph node metastasis or lymphadenitis model was established by hock injection of either luciferase-expressing 4T1 murine breast cancer cells or complete Freund's adjuvant in male BALB/c mice. At different time points after inoculation, bioluminescence imaging and T₂-weighted, diffusion-weighted, and SPIO-enhanced MRI were performed. Imaging findings were confirmed by histopathological staining.

Results

Size enlargement was observed in both TLNs and RLNs. At day 28, TLNs showed strong bioluminescence signal and bigger size than RLNs (p?<?0.01). At early stages up to day 21, both TLNs and RLNs appeared homogeneous on diffusion-weighted imaging. At day 28, TLNs showed heterogeneous apparent diffusion coefficient (ADC) map with significantly higher average ADC value of 0.41?±?0.03?×?10^?3mm²/s than that of RLNs (0.34?±?0.02?×?10^?3mm²/s; p?<?0.05). On SPIO-enhanced MRI, both TLNs and RLNs showed distinct T₂ signal reduction at day 21 after inoculation. At day 28, TLNs demonstrated partial uptake of the iron oxide particles, which was confirmed by Prussian blue staining.

Conclusions

Both diffusion-weighted and SPIO-enhanced MRI can distinguish tumor metastatic lymph nodes from reactive lymph nodes. However, neither method is able to detect tumor metastasis to the draining lymph nodes at early stages.     

Can a b value of 500 be substituted for a b value of 1000 in the characterization of focal liver lesions?

Purpose

Comparison of two different b values in diffusion-weighted magnetic resonance imaging (DWI) for characterization of focal liver lesions.

Methods

A total of 174 focal liver lesions from 100 patients were analyzed using two different b values (500 and 1000 s/mm²). The DWI with b values of 500 s/mm² (DWI500) and 1000 s/mm² (DWI1000) were analyzed using the Mann–Whitney test, kappa statistic, and paired t test with respect to image quality. The statistically significant differences between DWI500 and DWI1000 in the characterization of the lesions with respect to the cutoff ADC values were evaluated via χ ² test.

Results

DWI500 had the highest mean score in the qualitative evaluation of image quality (p < 0.0001) and the highest signal-to-noise ratio (8.7 ± 2.1; p < 0.0001). The sensitivity, specificity, and AUC for discriminating malignant from benign focal lesions on DWI500 and DWI1000 using cutoff ADC values of 1.54 × 10^?3 and 1.38 × 10^?3 s/mm² were 95.8%, 92.3%, 0.98, and 93.8%, 92.3%, 0.97, respectively. There was no statistically significant difference in sensitivity, specificity, and AUC values between DWI500 and DWI1000 with respect to the cutoff ADC values (p > 0.05).

Conclusions

The image quality of DWI500 was better than that of DWI1000, and there was no significant difference between DWI500 and DWI1000 in the characterization of the lesions with respect to the cutoff ADC values. The b value of 500 s/mm² can be substituted for the b value of 1000 s/mm² in the characterization of focal liver lesions.     

Comparison of Standardized Uptake Values in Normal Structures Between PET/CT and PET/MRI in an Oncology Patient Population

Purpose

The purpose of this study was to compare and correlate standardized uptake values (SUV) derived from magnetic resonance attenuation correction (MRAC) with those derived from computed tomography attenuation correction (CTAC) in an oncology patient population.

Procedures

The HIPAA-compliant study was approved by the Internal Review Board and all subjects gave written informed consent prior to inclusion in the study. Forty patients (mean age 61?±?15.1; 20 male) referred for clinically indicated 2-deoxy-2-[¹⁸F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) scans also underwent a PET/magnetic resonance imaging (MRI) examination. MRAC was performed using an automatic three-segment model. Regions of interest were drawn over eight normal structures in order to obtain SUVmax and SUVmean values. Spearman rank correlation coefficients (r) were calculated and two-tailed paired t tests were performed to compare the SUVmax and SUVmean values obtained from CTAC with those from MRAC.

Results

The mean time after FDG injection was 66?±?7 min for PET/CT and 117?±?15 min for PET/MRI examination. MRAC SUV values were significantly lower than the CTAC SUV values in mediastinal blood pool (p?<?0.001 for both SUVmax and SUVmean) and liver (p?=?0.01 for SUVmean). The MRAC SUV values were significantly higher in bone marrow (p?<?0.001 for both SUVmax and SUVmean), psoas major muscle (p?<?0.001 for SUVmax), and left ventricular myocardium (p?<?0.001 for SUVmax and p?=?0.01 for SUVmean). For the other normal structures, no significant difference was observed. When comparing SUV values generated from CTAC versus MRAC, high correlations between CTAC and MRAC were observed in myocardium (r?=?0.96/0.97 for SUVmax/mean), liver (r?=?0.68 for SUVmax), bone marrow (r?=?0.80/0.83 for SUVmax/mean), lung tissue (r?=?0.70 for SUVmax), and mediastinal blood pool (r?=?0.0.68/.069 for SUVmax/mean). Moderate correlations were found in lung tissue (r?=?0.67 for SUV mean), liver (r?=?0.66 for SUVmean), fat (r?=?0.48/0.53 for SUVmax/mean), psoas major muscle (r?=?0.54/0.58 for SUVmax/mean), and iliacus muscle (r?=?0.41 for SUVmax). Low correlation was found in iliacus muscle (r?=?0.32 for SUVmean).

Conclusions

Using the automatic three-segment model, our study showed high correlation for measurement of SUV values obtained from MRAC compared to those from CTAC, as the reference standard. Differences observed between MRAC and CTAC derived SUV values may be attributed to the time-delay between the PET/CT and PET/MRI scans or biologic clearance of radiotracer. Further studies are required to assess SUV measurements when performing different MR attenuation correction techniques.     

Comparison of [<Superscript>11</Superscript>C]Choline ([<Superscript>11</Superscript>C]CHO) and [<Superscript>18</Superscript>F]Bombesin (BAY 86-4367) as Imaging Probes for Prostate Cancer in a PC-3 Prostate Cancer Xenograft Model

Purpose

Carbon-11- and fluorine-18-labeled choline derivatives are commonly used in prostate cancer imaging in the clinical setting for staging and re-staging of prostate cancer. Due to a limited detection rate of established positron emission tomography (PET) tracers, there is a clinical need for innovative tumor-specific PET compounds addressing new imaging targets. The aim of this study was to compare the properties of [¹⁸F]Bombesin (BAY 86-4367) as an innovative biomarker for prostate cancer imaging targeting the gastrin-releasing peptide receptor and [¹¹C]Choline ([¹¹C]CHO) in a human prostate tumor mouse xenograft model by small animal PET/X-ray computed tomography (CT).

Procedures

We carried out a dual-tracer small animal PET/CT study comparing [¹⁸F]Bombesin and [¹¹C]CHO. The androgen-independent human prostate tumor cell line PC-3 was implanted subcutaneously in the flanks of nu/nu NMRI mice (n?=?10) (PET/CT measurements of two [¹¹C]Choline mice could not be analyzed due to technical reasons). [¹⁸F]Bombesin and [¹¹C]CHO PET/CT imaging was performed about 3–4 weeks after the implantation of PC-3 cells on two separate days. After the intravenous tail vein injection of 14 MBq [¹⁸F]Bombesin and 37 MBq [¹¹C]CHO, respectively, a dynamic study over 60 min was acquired in list mode using an Inveon animal PET/CT scanner (Siemens Medical Solutions). The sequence of [¹⁸F]Bombesin and [¹¹C]CHO was randomized. Image analysis was performed using summed images as well as dynamic data. To calculate static and dynamic tumor-to-muscle (T/M), tumor-to-blood (T/B), liver-to-blood (L/B), and kidney-to-blood (K/B) ratios, 4?×?4?×?4 mm³ volumes of interest (VOIs) of tumor, muscle (thigh), liver, kidney, and blood derived from transversal slices were used.

Results

The mean T/M ratio of [¹⁸F]Bombesin and [¹¹C]CHO was 6.54?±?2.49 and 1.35?±?0.30, respectively. The mean T/B ratio was 1.83?±?0.79 for [¹⁸F]Bombesin and 0.55?±?0.10 for [¹¹C]CHO. The T/M ratio as well as the T/B ratio for [¹⁸F]Bombesin were significantly higher compared to those for [¹¹C]CHO (p?<?0.001, respectively). Kidney and liver uptake was statistically significantly lower for [¹⁸F]Bombesin (K/B 3.41?±?0.81, L/B 1.99?±?0.38) compared to [¹¹C]CHO [K/B 7.91?±?1.85 (p?<?0.001), L/B 6.27?±?1.99 (p?<?0.001)]. The magnitudes of the time course of T/M and T/B ratios (T/M and T/B_dyn ratios) were statistically significantly different (showing a higher uptake of [¹⁸F]Bombesin compared to [¹¹C]CHO); additionally, also the change of the T/M and T/B ratios over time was significantly different between both tracers in the dynamic analysis (p?<?0.001, respectively). Furthermore, there was a statistically significantly different change of the K/B and L/B ratios over time between the two tracers in the dynamic analysis (p?=?0.026 and p?<?0.001, respectively).

Conclusions

[¹⁸F]Bombesin (BAY 86-4367) visually and semi-quantitatively outperforms [¹¹C]CHO in the PC-3 prostate cancer xenograft model. [¹⁸F]Bombesin tumor uptake was significantly higher compared to [¹¹C]CHO. [¹⁸F]Bombesin showed better imaging properties compared to the clinically utilized [¹¹C]CHO due to a higher tumor uptake as well as a lower liver and kidney uptake.

     

Pilot Study of a Novel 18F-labeled FSHR Probe for Tumor Imaging

Purpose

Follicle-stimulating hormone receptor (FSHR) is overexpressed in primary and metastatic tumor. Molecular imaging of FSHR is beneficial for prognosis and therapy of cancer. FSHβ(33–53) (YTRDLVYKDPARPKIQKTCTF), denoted as FSH1, is a FSHR antagonist. In the present study, maleimide-NOTA conjugate of FSH1 (NOTA-MAL-FSH1) was designed and labeled with [¹⁸F] aluminum fluoride. The resulting tracer, ¹⁸F-Al-NOTA-MAL-FSH1, was preliminarily evaluated in PET imaging of FSHR-positive tumor.

Procedures

NOTA-MAL-FSH1 was synthesized and radiolabeled with Al¹⁸F complex. The tumor-targeting potential and pharmacokinetic profile of the ¹⁸F-labeled compound were evaluated in vitro and in vivo using a PC3 human prostate tumor model.

Results

¹⁸F-Al-NOTA-MAL-FSH1 can be efficiently produced within 30 min with a non-decay-corrected yield of 48.6?±?2.1 % and a radiochemical purity of more than 95 %. The specific activity was at least 30 GBq/μmol. The radiotracer was stable in phosphate-buffered saline and human serum for at least 2 h. The IC₅₀ values of displacement ¹⁸F-Al-NOTA-MAL-FSH1 with FSH1 were 252?±?1.12 nM. The PC3 human prostate tumor xenografts were clearly visible with high contrast after injection of ¹⁸F-Al-NOTA-MAL-FSH1 via microPET. At 30, 60 and 120 min postinjection, the tumor uptakes were 2.98?±?0.29 % injected dose (ID)/g, 2.53?±?0.20 %ID/g and 1.36?±?0.12 %ID/g, respectively. Dynamic PET scanning showed that tumor uptake reached a plateau by about 6 min. Heart peaked earlier and then cleared quickly. Biodistribution studies confirmed that the normal organs except kidney uptakes were all below 1 %ID/g at 1 h p.i. The tumor-to-blood and tumor-to-muscle ratio at 10 min, 0.5, 1, and 2 h after injection were 1.64?±?0.36, 2.97?±?0.40, 9.31?±?1.06, and 13.59?±?2.33 and 7.05?±?1.10, 10.10?±?1.48, 16.17?±?3.29, and 30.88?±?4.67, respectively. The tracer was excreted mainly through the renal system, as evidenced by high levels of radioactivity in the kidneys. FSHR-binding specificity was also demonstrated by reduced tumor uptake of ¹⁸F-Al-NOTA-MAL-FSH1 after coinjection with an excess of unlabeled FSH1 peptide.

Conclusion

NOTA-MAL-FSH1 could be labeled rapidly and efficiently with ¹⁸F using one step method. Favorable preclinical data suggest that ¹⁸F-Al-NOTA-MAL-FSH1 may be a suitable radiotracer for the non-invasive visualization of FSHR positive tumor in vivo.     

Direct, Quantitative, and Noninvasive Imaging of the Transport of Active Agents Through Intact Brain with Positron Emission Tomography

Purpose

Our goal was to use positron emission tomography (PET) to analyze the movement of radiolabeled agents in tissue to enable direct measurement of drug delivery to the brain.

Procedures

Various ¹¹C- and ¹⁸?F-labeled compounds were delivered directly to an agarose phantom or rat striatum. Concentration profiles were extracted for analysis and fitted to diffusion models.

Results

Diffusion coefficients ranged from 0.075?±?0.0026 mm²/min ([¹⁸?F]fluoride ion, 18 Da) to 0.0016?±?0.0018 mm²/min ([¹⁸?F]NPB4-avidin, 68 kDa) and matched well with predictions based on molecular weight (R ²?=?0.965). The tortuosity of the brain extracellular space was estimated to be 1.56, with the tissue clearance halftime of each tracer in the brain varying from 19 to 41 min.

Conclusions

PET is an effective modality to directly quantify the movement of locally delivered drugs or drug carriers. This continuous, noninvasive assessment of delivery will aid the design of better drug delivery methods.     

Diffusion-weighted imaging (DWI) of adenomyosis and fibroids of the uterus

Purpose

Although magnetic resonance imaging is often able to distinguish between adenomyosis and fibroids, occasionally the imaging features of focal adenomyosis and fibroids overlap. Diffusion-weighted imaging (DWI) may provide useful information in differentiating pathologies. Therefore, the purpose of our study was to evaluate differences, if any, in the apparent diffusion coefficient (ADC) values of fibroids and adenomyosis.

Material and methods

Patients (n = 50) with uterine fibroids and adenomyosis (n = 43), who underwent pelvic MR imaging including DWI, were included in this IRB approved HIPPA compliant retrospective study. DWI was performed with b factors of 50, 400, and 800 s/mm using a 1.5 T scanner. ADC ROI measurements were placed over a fibroid, an area of adenomyosis, unaffected normal myometrium, skeletal muscle, and urine. Histogram analysis of ADC maps in 20 cases each of adenomyosis and fibroids was evaluated to assess the degree of tissue heterogeneity.

Results

The ADC values of adenomyosis and fibroids were compared using Student’s t test. The mean and the standard deviation of the ADC values of the control group were as follows: fibroid 0.64 ± 0.29, adenomyosis 0.86 ± 0.30, myometrium 1.39 ± 0.36, and urine 3.01 ± 0.2 × 10^?3 mm²/s. There was a statistically significant difference among the ADC values of normal myometrium and fibroids (p < 0.0001), normal myometrium and adenomyosis (p < 0.0001), and fibroids and adenomyosis (p < 0.001). Histogram analysis demonstrates less heterogeneity of adenomyosis as compared to fibroids.

Conclusion

The present study shows that ADC measurements have the potential to quantitatively differentiate between fibroids and adenomyosis.     

Biodistribution and Radiation Dosimetry of the Serotonin 5-HT6 Ligand [11C]GSK215083 Determined from Human Whole-Body PET

Purpose

We measured the whole-body distribution of IV-injected [¹¹C]GSK215083, a new 5-HT₆ antagonist PET tracer, as a function of time in adult subjects, in order to determine the radiation exposure.

Procedures

After injection with a single bolus of [¹¹C]GSK215083 (range 330?C367?MBq; mean 346?MBq), PET emission data were acquired for approximately 120?min in six subjects (three males and three females). Five organs were identified as exhibiting uptake above background. For these, regions of interest were delineated on emission images, and time?Cactivity curves (TAC) generated. Residence times were calculated as the area under the curve of the TAC, normalized to injected activities and standard values of organ volumes. Dosimetry calculations were then performed using the computer program OLINDA/EXM 1.0.

Results

The mean effective dose averaged over both males and females (±standard deviation) was estimated to be 7.7?±?1.0???Sv/MBq (male 7.0?±?0.4; female 8.5?±?0.6). For the effective dose equivalent, the corresponding values are 7.8?±?1.2???Sv/MBq (male 6.8?±?0.5; female 8.9?±?0.1). The organ receiving the highest dose was the lung, with an average equivalent dose of 25.6?±?6.9???Sv/MBq (male 20.8?±?5.6; female 30.4?±?4.4).

Conclusion

The estimated radiation dose for [¹¹C]GSK215083 is consistent with those for other neuroreceptor ligands labeled with carbon-11. The somewhat higher dose estimate for females compared to males may reflect the difference in observed residence times and representative differences in the male and female phantoms used for dosimetry calculations. Based on conventionally accepted dose limits, [¹¹C]GSK215083 may be used for multiple PET scans in the same subject.     

Value of diffusion-weighted MR imaging in the diagnosis of lymph node metastases in patients with cholangiocarcinoma

Purpose

To evaluate diffusion-weighted MR imaging (DWI) in the diagnosis of lymph node metastases in patients with cholangiocarcinoma.

Methods

In 24 patients with cholangiocarcinoma, MR imaging of the upper abdomen was performed prior to surgery at 1.5 T using a respiratory-triggered single-shot echo-planar imaging (SSEPI) sequence (b values: 50, 300, and 600 s/mm²). ADC (apparent diffusion coefficient) values and diameters of regional lymph nodes (LN) were determined. Subsequently, in all patients, surgical exploration and/or resection of the primary tumor and regional LN dissection were performed. Imaging results were correlated with results of histopathologic analysis. ADC values and diameters of benign and malignant LN were compared using the Mann–Whitney U test. In addition, a ROC (receiver operating characteristic curve) analysis was performed.

Results

The mean ADC value (×10^?3 mm²/s) of metastatic LN (1.21 ± 0.15) was significantly lower than that of benign LN (1.62 ± 0.33, p < 0.001) while there was no significant difference in the mean diameter of malignant (16.8 ± 5.4 mm) and benign LN (14.1 ± 4.0 mm; p = 0.09). Using an ADC value of 1.25 × 10^?3 mm²/s as threshold, 91.4% of LN were correctly classified as benign or malignant with a sensitivity/specificity of 83.3%/92.8% and a positive/negative predictive value of 66.7%/96.7%. The area under the ROC curve was 0.93.

Conclusion

DWI using a respiratory-triggered SSEPI sequence, according to our preliminary experience, is a promising imaging modality in the differentiation of benign and malignant LN in patients with cholangiocarcinoma.

     

Fully Automated Production of 11C-Doxepin for PET Imaging Histamine H1 Receptor

Objectives

¹¹C-Doxepin is an established positron emission tomography (PET) probe for imaging the histamine H1 receptor, which is associated with various neurological disorders and allergic diseases. A fully automated current Good Manufacturing Practices (cGMP)-compliant radiosynthesis is therefore desirable in order to facilitate clinical PET studies. We report here a fully automated production method for ¹¹C-doxepin using a multipurpose PET module for clinical use.

Methods

¹¹C-Doxepin was radiosynthesized by N-[¹¹C]methylation of nordoxepin using [¹¹C]methyl iodide in DMF solvent, and then purified by HPLC, and finally reformulated with solid phase extraction (SPE) using a cGMP-compliant automated multipurpose PET module developed in house. The final product was analyzed and subjected to quality control according to current US Pharmacopeia requirements.

Results

The radiochemical yield (decay corrected) of ¹¹C-doxepin for clinical use was 47.0?±?5.2% (n?=?12) based on [¹¹C]methyl iodide, moreover the radiochemical purity of ¹¹C-doxepin was more than 97.5% with 1,200?±?500?Ci/mmol specific activity(end of production). The total production time of ¹¹C-doxepin was 37?min from end of bombardment (EOB) with the final product passing all tests under cGMP requirements for clinical use.

Conclusions

A simplified and reliable fully automated production of ¹¹?C-doxepin for clinical use was developed, allowing the synthesis of the tracer with high yield using a cGMP-compliant module and procedure. The success of this approach could make the PET tracer ¹¹?C-doxepin more accessible for clinical studies.     

[68Ga]-Albumin-PET in the Monitoring of Left Ventricular Function in Murine Models of Ischemic and Dilated Cardiomyopathy: Comparison with Cardiac MRI

Purpose

The purpose of this study is to evaluate left ventricular functional parameters in healthy mice and in different murine models of cardiomyopathy with the novel blood pool (BP) positron emission tomography (PET) tracer [⁶⁸Ga]-albumin.

Procedures

ECG-gated microPET examinations were obtained in healthy mice, and mice with dilative (DCM) and ischemic cardiomyopathy (ICM) using the novel BP tracer [⁶⁸Ga]-albumin (Alb_BP), as well as [¹⁸F]-FDG microPET. Cine-magnetic resonance imaging (MRI) examination performed on a clinical 1.5-T MRI provided the reference standard measurements.

Results

When considering the combined group of healthy controls, DCM and ICM Alb_BP-PET significantly overestimated the magnitudes of EDV (Alb_BP, 181?±?86 μl; cine-MRI, 125?±?80 μl; P?<?0.001) and ESV (Alb_BP, 136?±?92 μl; cine-MRI, 96?±?77 μl; P?<?0.001), whereas the EF (Alb_BP, 31?±?16 %; cine-MRI, 33?±?21 %; P?=?0.910) matched closely to cine-MRI results, as did findings with [¹⁸F]-FDG. High correlations were found between the measured cardiac parameters (EDV: R?=?0.978, ESV: R?=?0.989, and LVEF: R?=?0.992).

Conclusions

Measuring left ventricular function in mice with [⁶⁸Ga]-albumin BP PET is feasible and showed a high correlation compared to cine-MRI, which was used as a reference standard.     

Longitudinal PET Imaging of Doxorubicin-Induced Cell Death with 18F-Annexin V

Purpose

This study aims to apply longitudinal positron emission tomography (PET) imaging with ¹⁸?F-Annexin V to visualize and evaluate cell death induced by doxorubicin in a human head and neck squamous cell cancer UM-SCC-22B tumor xenograft model.

Procedures

In vitro toxicity of doxorubicin to UM-SCC-22B cells was determined by a colorimetric assay. Recombinant human Annexin V protein was expressed and purified. The protein was labeled with fluorescein isothiocyanate for fluorescence staining and ¹⁸?F for PET imaging. Established UM-SCC-22B tumors in nude mice were treated with two doses of doxorubicin (10?mg/kg each dose) with 1?day interval. Longitudinal ¹⁸?F-Annexin V PET was performed at 6?h, 24?h, 3?days, and 7?days after the treatment started. Following PET imaging, direct tissue biodistribution study was performed to confirm the accuracy of PET quantification.

Results

Two doses of doxorubicin effectively inhibited the growth of UM-SCC-22B tumors by inducing cell death including apoptosis. The cell death was clearly visualized by ¹⁸?F-Annexin V PET. The peak tumor uptake, which was observed at day 3 after treatment started, was significantly higher than that in the untreated tumors (1.56?±?0.23 vs. 0.89?±?0.31%ID/g, p?<?0.05). Moreover, the tumor uptake could be blocked by co-injection of excess amount of unlabeled Annexin V protein. At day 7 after treatment, the tumor uptake of ¹⁸?F-Annexin had returned to baseline level.

Conclusions

¹⁸?F-Annexin V PET imaging is sensitive enough to allow visualization of doxorubicin-induced cell death in UM-SCC-22B xenograft model. The longitudinal imaging with ¹⁸?F-Annexin will be helpful to monitor early response to chemotherapeutic anti-cancer drugs.     

Dynamic Changes of FDG Uptake and Clearance in Normal Tissues

Purpose

This study aims to evaluate dynamic 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) uptake in normal tissues.

Procedures

Thirty male patients underwent FDG positron emission tomography (PET)/computed tomography imaging at 1, 2, and 3 h after tracer injection. Standardized uptake values (SUV) were obtained in regions of interest of normal tissues.

Results

The aorta (blood pool), liver, and spleen FDG activity demonstrated significantly and continuously decreased activity from 1 to 2 and 2 to 3 h, while FDG uptake in the lungs, pancreas, lymph nodes, and skeletal muscle decreased from 1 to 2 h only. In contrast, the left ventricular myocardium demonstrated two patterns of dynamic changes: myocardium with higher FDG uptake (SUV_max?≥?3.25) on the initial images had more remarkable increased activity on the delayed images, while myocardium with lower FDG uptake (SUV_max?<?3.25) on the initial imaging had no increased uptake on delayed imaging. Increased FDG uptake was also observed in the bones on the delayed images. No significant changes of FDG uptake were noted in the parotid gland, thyroid gland, and prostate gland.

Conclusions

These findings may help nuclear medicine physicians when comparing images performed at different time points, when using FDG uptake in internal reference regions as a relative indicator of FDG uptake in a specific lesion, and when reading a delayed FDG PET imaging.     

Positron Emission Tomography of 64Cu-DOTA-Rituximab in a Transgenic Mouse Model Expressing Human CD20 for Clinical Translation to Image NHL

Purpose

This study aims to evaluate ⁶⁴Cu-DOTA-rituximab (PETRIT) in a preclinical transgenic mouse model expressing human CD20 for potential clinical translation.

Procedures

⁶⁴Cu was chelated to DOTA-rituximab. Multiple radiolabeling, quality assurance, and imaging experiments were performed. The human CD20 antigen was expressed in B cells of transgenic mice (CD20TM). The mice groups studied were: (a) control (nude mice, n?=?3) that received 7.4?MBq/dose, (b) with pre-dose (CD20TM, n?=?6) received 2?mg/kg pre-dose of cold rituximab prior to PETRIT of 7.4?MBq/dose, and (c) without pre-dose (CD20TM, n?=?6) PETRIT alone received 7.4?MBq/dose. Small animal PET was used to image mice at various time points (0, 1, 2, 4, 24, 48, and 72?h). The OLINDA/EXM software was used to determine the human equivalent dose for individual organs.

Results

PETRIT was obtained with a specific activity of 545?±?38.91?MBq/nmole, radiochemical purity >95%, and immunoreactivity >75%. At 24?h, spleenic uptake of PETRIT%ID/g (mean?±?STD) with and without pre-dose was 1.76?±?0.43% and 16.5?±?0.45%, respectively (P value?=?0.01). Liver uptake with and without pre-dose was 0.41?±?0.51% and 0.52?±?0.17% (P value?=?0.86), respectively. The human equivalents of highest dose organs with and without pre-dose are osteogenic cells at 30.8?±?0.4???Sv/MBq and the spleen at 99?±?4???Sv/MBq, respectively.

Conclusions

PET imaging with PETRIT in huCD20 transgenic mice provided human dosimetry data for eventual applications in non-Hodgkins lymphoma patients.     

In Vitro and In Vivo Characterization of Two C-11-Labeled PET Tracers for Vesicular Acetylcholine Transporter

Purpose

The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. Herein, two potent and selective ¹¹C-labeled VAChT inhibitors were evaluated in rodents and nonhuman primates for imaging VAChT in vivo.

Procedures

For both (?)-[¹¹C]2 and (?)-[¹¹C]6, biodistribution, autoradiography, and metabolism studies were performed in male Sprague Dawley rats. Positron emission tomography (PET) brain studies with (?)-[¹¹C]2 were performed in adult male cynomolgus macaques; 2 h dynamic data was acquired, and the regions of interest were drawn by co-registration of the PET images with the MRI.

Results

The resolved enantiomers (?)-2 and (?)-6 were very potent and selective for VAChT in vitro (K _i ?35-fold selectivity for VAChT vs. σ receptors); both radioligands, (?)-[¹¹C]2 and (?)-[¹¹C]6, demonstrated high accumulation in the VAChT-enriched striatum of rats. (?)-[¹¹C]2 had a higher striatum to cerebellum ratio of 2.4-fold at 60 min; at 30 min, striatal uptake reached 0.550?±?0.086 %ID/g. Uptake was also specific and selective; following pretreatment with (±)-2, striatal uptake of (?)-[¹¹C]2 in rats at 30 min decreased by 50 %, while pretreatment with a potent sigma ligand had no significant effect on striatal uptake in rats. In addition, (?)-[¹¹C]2 displayed favorable in vivo stability in rat blood and brain. PET studies of (?)-[¹¹C]2 in nonhuman primates indicate that it readily crosses the blood-brain barrier (BBB) and provides clear visualization of the striatum; striatal uptake reaches the maximum at 60 min, at which time the target to nontarget ratio reached ~2-fold.

Conclusions

The radioligand (?)-[¹¹C]2 has high potential to be a suitable PET radioligand for imaging VAChT in the brain of living subjects.     

In Vitro and In Vivo Structure–Property Relationship of 68Ga-Labeled Schiff Base Derivatives for Functional Myocardial PET Imaging

Purpose

SPECT (e.g., with ^99mTc-sestamibi) is routinely used for imaging myocardial damage, even though PET could offer a higher spatial resolution. Using the generator-gained isotope ⁶⁸Ga would allow a rapid supply of the tracer in the diagnostic unit. For this reason, the aim of the study was to develop ⁶⁸Ga-labeled PET tracers based on different Schiff base amines and to evaluate the cardiomyocyte uptake in vitro as well as the biodistribution of the tracers in vivo.

Procedures

Fifteen different Schiff bases (basing on 3 different backbones) were synthesized and labeled with ⁶⁸Ga. Lipophilicity varied between 0.87?±?0.24 and 2.72?±?0.14 (logD value). All tracers were positively charged and stable in plasma and apo-transferrin solution. In vitro uptake into cardiomyocytes was assessed in HL-1 cells in the absence and presence of the ionophor valinomycin. In vivo accumulation in the heart and in various organs was assessed by small animal PET imaging as well as by ex vivo biodistribution. The results were compared with ^99mTc-sestamibi and ¹⁸F-flurpiridaz.

Results

All cationic Schiff bases were taken up into cardiomyocytes but the amount varied by a factor of 10. When destroying the membrane potential, the cellular uptake was markedly reduced in most of the tracers, indicating the applicability of these tracers for identifying ischemic myocardium. PET imaging revealed that the in vivo myocardial uptake reached a constant value approximately 10 min after injection but the intracardial amount of the tracer varied profoundly (SUV 0.46 to 3.35). The most suitable tracers showed a myocardial uptake which was comparable to that of ^99mTc-sestamibi.

Conclusions

⁶⁸Ga-based Schiff bases appear suitable for myocardial PET images with uptake comparable to ^99mTc-sestamibi but offering higher spatial resolution. By systematical variation of the backbone and the side chains, tracers with optimal properties can be identified for further clinical evaluation.     

Evaluation of Rho-Kinase Activity in Mice Brain Using N-[11C]Methyl-hydroxyfasudil with Positron Emission Tomography

Purpose

Rho is a small molecular weight GTP-binding protein and works as a molecular shuttling switch between an active (GTP-bound) and inactive (GDP-bound) state. Rho is known to be involved in cell motility, cell adhesion, and cytokinesis through actin cytoskeleton reorganization. The GTP-bound form of Rho interacts with its specific downstream target, triggering intracellular signaling cascades. Rho effectors such as Rho-kinases have been isolated on the basis of their selective binding to the GTP-bound form of Rho. Rho-kinase is thought to have an important role in the pathogenesis of a variety of neurological diseases because activation of the Rho/Rho-kinase pathway has been observed in various central nervous system disorders. Previous histochemical studies have shown multiple molecular mechanisms for the regulation of Rho-kinase. Neuroimaging of Rho/Rho-kinase has rarely been studied because of a lack of appropriate radiotracers. Recently, N-[¹¹C]methyl-hydroxyfasudil, a new radiotracer for positron emission tomography (PET), has been introduced to measure Rho-kinase activity. In this study, the regional distribution and kinetics of N-[¹¹C]methyl-hydroxyfasudil were investigated in the brains of mice.

Procedures

A 90-min dynamic scan was performed following intravenous infusion of N-[¹¹C]methyl-hydroxyfasudil.

Results

The uptake of N-[¹¹C]methyl-hydroxyfasudil reached a maximum within 5 min and gradually decreased in all organs. The standard uptake values (SUVs) in the brain, liver, and kidney on average between 30 to 60 min were 0.17?±?0.03, 0.76?±?0.18, and 0.62?±?0.18 and from 60 to 90 min were 0.15?±?0.01, 0.69?±?0.33, and 0.64?±?0.17, respectively. N-[¹¹C]Methyl-hydroxyfasudil showed a widespread distribution throughout the brain, with low levels of radioactivity. Radioactivity concentration in plasma at 90 min after injection of N-[¹¹C]methyl-hydroxyfasudil resulted in SUVs in the control and fasudil pretreatment of 0.0013 and 0.0023?±?0.0008, respectively. Compared to normal control mice, about twofold higher radioactivity concentration was observed in fasudil-pretreated mice. In a cold brain injury mouse model, accumulation of N-[¹¹C]methyl-hydroxyfasudil was slightly higher at the injury site than that at the control site, and the difference was statistically significant in the “24 h after injury” group (P?<?0.05).

Conclusions

These results suggest that following brain injury, N-[¹¹C]methyl-hydroxyfasudil binds to the active form of Rho-kinase. PET imaging using N-[¹¹C]methyl-hydroxyfasudil could provide new insights into the pathophysiology of a variety of neurological disorders including stroke, inflammatory diseases, demyelinating diseases, Alzheimer's disease, and neuropathic pain.     

Pancreatic adenocarcinoma: a pilot study of quantitative perfusion and diffusion-weighted breath-hold magnetic resonance imaging

Purpose

To confirm the feasibility of breath-hold DCE-MRI and DWI at 3T to obtain the intra-abdominal quantitative physiologic parameters, K ^trans, k _ep, and ADC, in patients with untreated pancreatic ductal adenocarcinomas.

Methods

Diffusion-weighted single-shot echo-planar imaging (DW-SS-EPI) and dynamic contrast-enhanced (DCE) MRI were used for 16 patients with newly diagnosed biopsy-proven pancreatic ductal adenocarcinomas. K ^trans, k _ep, and apparent diffusion coefficient (ADC) values of pancreatic tumors, non-tumor adjacent pancreatic parenchyma (NAP), liver metastases, and normal liver tissues were quantitated and statistically compared.

Results

Fourteen patients were able to adequately hold their breath for DCE-MRI, and 15 patients for DW-SS-EPI. Four patients had liver metastases within the 6 cm of Z axis coverage centered on the pancreatic primary tumors. K ^trans values (10^?3 min^?1) of primary pancreatic tumors, NAP, liver metastases, and normal liver tissues were 7.3 ± 4.2 (mean ± SD), 25.8 ± 14.9, 8.1 ± 5.9, and 45.1 ± 15.6, respectively, k _ep values (10^?2 min^?1) were 3.0 ± 0.9, 7.4 ± 3.1, 5.2 ± 2.0, and 12.1 ± 2.8, respectively, and ADC values (10^?3 mm²/s) were 1.3 ± 0.2, 1.6 ± 0.3, 1.1 ± 0.1, and 1.3 ± 0.1, respectively. K ^trans, k _ep, and ADC values of primary pancreatic tumors were significantly lower than those of NAP (p < 0.05), while K ^trans and k _ep values of liver metastases were significantly lower than those of normal liver tissues (p < 0.05).

Conclusions

3T breath-hold quantitative physiologic MRI is a feasible technique that can be applied to a majority of patients with pancreatic adenocarcinomas.     

Apparent diffusion coefficient quantification as an early imaging biomarker of response and predictor of survival following yttrium-90 radioembolization for unresectable infiltrative hepatocellular carcinoma with portal vein thrombosis

Purpose

To investigate early diffusion-weighted imaging (DWI) at 30-days post-yttrium-90 (Y-90) radioembolization as a predictor of treatment response and survival in unresectable infiltrative hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT).

Materials and methods

In a prospective study, 18 consecutive patients with unresectable infiltrative HCC and PVT underwent Y-90 therapy. MR imaging was obtained pre Y-90, and at 1 and 3 months post-therapy with DWI fat-suppressed tri-directional diffusion gradient (b = 50, 400, 800 s/mm²). Response was evaluated using target mRECIST and EASL. Relative change in apparent diffusion coefficient (ADC) value of tumors was evaluated. Statistical analysis using receiver operator characteristic curves was performed. Paired t test and Pearson correlation coefficient (r) were used to assess intra- and inter-observer variability. Survival analysis was performed using Kaplan-Meier estimation and log-rank test.

Results

Mean ADC values of all HCC’s at baseline and at 30-days post-Y90 therapy was 0.86 × 10^?3 and 1.17×10^?3 mm²/s, respectively (p < 0.001). Tumors with objective response by mRECIST had significantly increased ADC value when compared to “non-responders” (1.27 vs. 1.05×10^?3 mm²/s, p = 0.002). A >30% increase in ADC value at 30-days was found to be at least 90% sensitive in predicting response at 90 days. A >30% increase in ADC value at 30-days predicted significantly prolonged survival.

Conclusion

A 30% increase in ADC value at 30-days measured post Y90 is a reproducible early imaging response biomarker predicting tumor response and prolonged survival following Y-90 therapy in infiltrative HCC with PVT.