[<Superscript>89</Superscript>Zr]Trastuzumab: Evaluation of Radiation Dosimetry,Safety, and Optimal Imaging Parameters in Women with HER2-Positive Breast Cancer

Purpose

The purpose of the present study is to evaluate safety, human radiation dosimetry, and optimal imaging time of [⁸⁹Zr]trastuzumab in patients with HER2-positive breast cancer.

Procedures

Twelve women with HER2-positive breast cancer underwent [⁸⁹Zr]trastuzumab positron emission tomography (PET)/X-ray computed tomography (CT) twice within 7 days post-injection. Biodistribution data from whole-torso PET/CT images and organ time-activity curves were created using data from all patients. Human dosimetry was calculated using OLINDA with the adult female model.

Results

High-quality images and the greatest tumor-to-nontumor contrast were achieved with images performed 5?±?1 day post-injection. Increased [⁸⁹Zr]trastuzumab uptake was seen in at least one known lesion in ten patients. The liver was the dose-limiting organ (retention of ～12 % of the injected dose and average dose of 1.54 mSv/MBq). The effective dose was 0.47 mSv/MBq. No adverse effects of [⁸⁹Zr]trastuzumab were encountered.

Conclusion

[⁸⁹Zr]trastuzumab was safe and optimally imaged at least 4 days post-injection. The liver was the dose-limiting organ.

     

Biodistribution and Radiation Dosimetry of [<Superscript>18</Superscript>F]Mefway in Humans

Purpose

[¹⁸F]Mefway is a positron emission tomography (PET) radioligand for quantification of the brain serotonin 1A (5-HT_1A) receptor density. The purpose of this study was to evaluate the radiation safety of [¹⁸F]Mefway in humans.

Procedures

Six healthy volunteers (three males and three females) were whole-body PET scanned for 114 min after injection of [¹⁸F]Mefway (226?±?35 MBq). Estimated radiation doses were determined by the OLINDA/EXM software.

Results

[¹⁸F]Mefway was safe and well tolerated by all subjects. Residence time ranges from 0 (gallbladder) to 0.822 h (urinary bladder wall). While the estimated radiation doses in the reproductive and blood-forming organs were below 13.35–22.87 μSv/MBq, radiation dose in the urinary bladder wall was 471 μSv/MBq. The mean effective dose was 40.23?±?6.63 μSv/MBq.

Conclusion

For a typical single injection of 185 MBq (5 mCi), the dose will result in 87.1 mSv for the urinary bladder wall. To reduce radiation burden, the bladder voiding can be used before [¹⁸F]Mefway PET scan.

     

Predictive Value of Asphericity in Pretherapeutic [<Superscript>111</Superscript>In]DTPA-Octreotide SPECT/CT for Response to Peptide Receptor Radionuclide Therapy with [<Superscript>177</Superscript>Lu]DOTATATE

Purpose

The purpose of this study was to assess the value of the spatial heterogeneity of somatostatin receptor (SSR) volume, quantified as asphericity (ASP), and to predict response to peptide receptor radionuclide therapy (PRRT) in patients with metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN).

Procedures

From June 2011 to May 2013, patients suffering from GEP-NEN who underwent pretherapeutic [¹¹¹In-DTPA⁰]octreotide scintigraphy (Octreoscan®) prior to [¹⁷⁷Lu-DOTA⁰-Tyr³]octreotate ([¹⁷⁷Lu]DOTATATE)-PRRT were enrolled in this retrospective evaluation. SSR expression in 20 NEN patients was qualitatively and quantitatively assessed using the Krenning score, the metastasis to liver uptake ratio (M/L ratio), and ASP at baseline. Response to PRRT was evaluated based on lesions, which were classified as responding lesions (RL) and non-responding lesions (NRL) after 4- and 12-month follow-ups. The values of the Krenning score, M/L ratio, and ASP for response prediction were compared by using the Mann-Whitney U test, Kruskal-Wallis test, and receiver operating characteristic (ROC) curves.

Results

Seventy-seven metastases (liver, n = 40; lymph node, n = 24; bone, n = 11; pancreas, n = 2) showed SSR expression. A higher ASP level was significantly associated with poorer response at both time points. ROC analyses revealed the highest area under the curve (AUC) for discrimination between RL and NRL for ASP after 4 months (AUC 0.97; p = 0.019) and after 12 months (AUC 0.96; p < 0.001), followed by the Krenning score (AUC 0.74; p = 0.082 and AUC 0.85; p < 0.001, respectively) and M/L ratio (AUC 0.77; p = 0.107 and AUC 0.82; p < 0.001). The optimal cutoff value for ASP was 5.12 % (sensitivity, 90 %; specificity, 93 %).

Conclusion

Asphericity of SSR-expressing lesions in pretherapeutic single-photon emission computed tomography with integrated computed tomography (SPECT/CT) is a promising parameter for predicting response to PRRT in gastroenteropancreatic neuroendocrine neoplasms.

     

Preclinical Evaluation of 4-[<Superscript>18</Superscript>F]Fluoroglutamine PET to Assess ASCT2 Expression in Lung Cancer

Purpose

Alanine-serine-cysteine transporter 2 (ASCT2) expression has been demonstrated as a promising lung cancer biomarker. (2S,4R)-4-[¹⁸F]Fluoroglutamine (4-[¹⁸F]fluoro-Gln) positron emission tomography (PET) was evaluated in preclinical models of non-small cell lung cancer as a quantitative, non-invasive measure of ASCT2 expression.

Procedures

In vivo microPET studies of 4-[¹⁸F]fluoro-Gln uptake were undertaken in human cell line xenograft tumor-bearing mice of varying ASCT2 levels, followed by a genetically engineered mouse model of epidermal growth factor receptor (EGFR)-mutant lung cancer. The relationship between a tracer accumulation and ASCT2 levels in tumors was evaluated by IHC and immunoblotting.

Result

4-[¹⁸F]Fluoro-Gln uptake, but not 2-deoxy-2-[¹⁸F]fluoro-D-glucose, correlated with relative ASCT2 levels in xenograft tumors. In genetically engineered mice, 4-[¹⁸F]fluoro-Gln accumulation was significantly elevated in lung tumors, relative to normal lung and cardiac tissues.

Conclusions

4-[¹⁸F]Fluoro-Gln PET appears to provide a non-invasive measure of ASCT2 expression. Given the potential of ASCT2 as a lung cancer biomarker, this and other tracers reflecting ASCT2 levels could emerge as precision imaging diagnostics in this setting.

     

Comparison of [<Superscript>14</Superscript>C]FMAU, [<Superscript>3</Superscript>H]FEAU, [<Superscript>14</Superscript>C]FIAU,and [<Superscript>3</Superscript>H]PCV for Monitoring Reporter Gene Expression of Wild Type and Mutant Herpes Simplex Virus Type 1 Thymidine Kinase in Cell Culture

Purpose To assess the optimal reporter probe/reporter gene combination for monitoring herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression, we compared the cellular uptake of 1-(2′-fluoro-2′-deoxy-d-arabinofuranosyl)-5-methyluracil (FMAU), 2′-fluoro-2′-deoxyarabinofuranosyl-5-ethyluracil (FEAU), 2′-fluoro-2′-deoxy-β-d-arabinofuranosyl-5-iodouracil (FIAU) and penciclovir (PCV) in both HSV1-tk and HSV1-sr39tk expressing cells. Procedures For stably transfected cell studies, C6 rat glioma cells, C6 HSV1-tk transfectant, C6 mutant HSV1-sr39tk transfectant, rat Morris hepatoma cells (MH3924A), and MH3924A HSV1-tk transfectant cells were used. For adenoviral infection studies, C6 rat glioma cells were exposed to serial titers of AdCMV–HSV1-tk, AdCMV–HSV1-sr39tk, or AdCMV–fluc for 24 hours. These cells were incubated with [¹⁴C]FMAU, [³H]FEAU, [¹⁴C]FIAU, and [³H]PCV, and cellular uptake of radioactivity was measured. Results [³H]FEAU exhibited the highest or second highest accumulation and the most selectivity regardless of the mode of gene transfer for both HSV1-tk and mutant HSV1-sr39tk reporter genes. Conclusion This combination of high accumulation and high selectivity for both HSV1-tk and HSV1-sr39tk makes suitably radiolabeled FEAU a promising candidate as a radiotracer for imaging HSV1-tk/HSV1-sr39tk gene expression in living subjects.     

Coupled Imaging with [<Superscript>18</Superscript>F]FBB and [<Superscript>18</Superscript>F]FDG in AD Subjects Show a Selective Association Between Amyloid Burden and Cortical Dysfunction in the Brain

Purpose

The present study was aimed to investigate the relationships between dysfunction of cortical glucose metabolism as detectable by means of 2-deoxy-2-[¹⁸F]fluoro -D-glucose ([¹⁸F]FDG) positron emission tomography/x-ray computed tomography (PET/CT) and amyloid burden as detectable by means of 4-{(E)-2-[4-(2-{2-[2-[¹⁸F]fluoroethoxy]ethoxy}ethoxy)phenyl]vinyl}-N-methylaniline (florbetaben; [¹⁸F]FBB) in a group of patients affected by Alzheimer’s disease (AD).

Procedures

We examined 38 patients newly diagnosed with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a PET/CT scan using both [¹⁸F]FDG and [¹⁸F]FBB with an average interval of 1 month. We used statistical parametric mapping (SPM8) implemented in Matlab R2012b and WFU pickatlas for the definition of a region of interest (ROI) mask including the whole cortex. These data were then normalized on the counts of the cerebellum and then used for a regression analysis on [¹⁸F]FDG scans in SPM. Furthermore, 58 control subjects were used as control group for [¹⁸F]FDG PET/CT scans.

Results

SPM analysis in AD patients showed a significant negative correlation between [¹⁸F] FBB and [¹⁸F] FDG uptake in temporal and parietal lobes bilaterally. Of note, these areas in AD patients displayed a marked glucose hypometabolism compared to control group.

Conclusions

Combined imaging with [¹⁸F]FBB and [¹⁸FFDG shows that amyloid burden in the brain is related to cortical dysfunction of temporal and parietal lobes in AD.

     

Preliminary PET/CT Imaging with Somatostatin Analogs [<Superscript>68</Superscript>Ga]DOTAGA-TATE and [<Superscript>68</Superscript>Ga]DOTAGA-TOC

Purpose

Somatostatin receptor positron emission tomography/X-ray computed tomography (SSTR-PET/CT) is a well-established technique for staging and detection of neuroendocrine tumors (NETs). Ga-68-labeled DOTA-conjugated octreotide analogs are the privileged radiotracers for diagnosis and therapeutic monitoring of NETs. Hence, we were interested in assessing the influence of promising, newer variant DOTAGA on the hydrophilicity, pharmacokinetics, and lesion pick-up of somatostatin analogs. Herein, the potential of ([⁶⁸Ga]DOTAGA, Tyr³, Thr⁸) octreotide ([⁶⁸Ga]DOTAGA-TATE) and ([⁶⁸Ga]DOTAGA, Tyr³) octreotide ([⁶⁸Ga]DOTAGA-TOC) as NET imaging agents has been investigated.

Procedures

Amenability of [⁶⁸Ga]DOTAGA-(TATE/TOC) to kit-type formulation has been demonstrated. Biodistribution studies were carried out in normal rats at 1 h post-injection (p.i.). [⁶⁸Ga]DOTAGA-(TATE/TOC) PET/CT scans were carried out in patients (70–170 MBq, 1 h p.i.) with histologically confirmed well-differentiated NETs.

Results

[⁶⁸Ga]DOTAGA-TATE exhibited hydrophilicity similar to [⁶⁸Ga]DOTA-TATE (log P = ?3.51 vs ?3.69) whereas [⁶⁸Ga]DOTAGA-TOC was more hydrophilic than [⁶⁸Ga]DOTA-TOC (log P = ?3.27 vs ?2.93). [⁶⁸Ga]DOTAGA-TATE and [⁶⁸Ga]DOTA-TATE showed almost identical blood and kidney uptake in normal rats whereas significantly fast clearance (p < 0.05) of [⁶⁸Ga]DOTAGA-TATE was observed from other non-specific organs (liver, lungs, spleen, intestine). [⁶⁸Ga]DOTAGA-TOC also demonstrated rapid clearance from blood and kidneys (p < 0.05) in comparison to [⁶⁸Ga]DOTA-TOC. The metastatic lesions in NET patients were well identified by [⁶⁸Ga]DOTAGA-TATE and [⁶⁸Ga]DOTAGA-TOC.

Conclusion

The phenomenal analogy was observed between [⁶⁸Ga]DOTAGA-TATE and [⁶⁸Ga]DOTA-TATE as well as between [⁶⁸Ga]DOTAGA-TOC and [⁶⁸Ga]DOTA-TOC in biodistribution studies in rats. The good lesion detection ability of the two radiotracers indicates their potential as NET imaging radiotracers.

     

Human Radiation Dosimetry of [<Superscript>18</Superscript>F]AV-1451(T807) to Detect Tau Pathology

Purpose

[¹⁸F]AV-1451 is a positron emission tomography (PET) radioligand for detecting paired helical filament tau. Our aim was to estimate the radiation dose of [¹⁸F]AV-1451 in humans.

Procedures

Whole-body PET scans were acquired for six healthy volunteers (three male, three female) for 128 min after injection of [¹⁸F]AV-1451 (268?±?31 MBq). Radiation doses were estimated using the OLINDA/EXM software.

Results

The estimated organ doses ranged from 7.81 to 81.2 μSv/MBq. The critical organ for radiation burden was the liver. Radiation doses to the reproductive and blood-forming organs were 14.15, 8.43, and 18.35 μSv/MBq for the ovaries, testes, and red marrow, respectively. The mean effective dose was 22.47?±?3.59 μSv/MBq.

Conclusions

A standard single injection of 185 MBq (5 mCi) results in an effective dose of 4.7 mSv in a healthy subject. Therefore, [¹⁸F]AV-1451 could be used in multiple PET scans of the same subject per year.

     

Evaluation of Pancreatic VMAT2 Binding with Active and Inactive Enantiomers of [<Superscript>18</Superscript>F]FP-DTBZ in Healthy Subjects and Patients with Type 1 Diabetes

Purpose

Previous studies demonstrated the utility of [¹⁸F]fluoropropyl-(+)-dihydrotetrabenazine ([¹⁸F]FP-(+)-DTBZ) as a positron emission tomography (PET) radiotracer for the vesicular monoamine transporter type 2 (VMAT2) to quantify beta cell mass in healthy control (HC) and type 1 diabetes mellitus (T1DM) groups. Quantification of specific binding requires measurement of non-displaceable uptake. Our goal was to identify a reference tissue (renal cortex or spleen) to quantify pancreatic non-specific binding of [¹⁸F]FP-(+)-DTBZ with the inactive enantiomer, [¹⁸F]FP-(?)-DTBZ. This was the first human study of [¹⁸F]FP-(?)-DTBZ.

Procedures

Six HCs and four T1DM patients were scanned on separate days after injection of [¹⁸F]FP-(+)-DTBZ or [¹⁸F]FP-(?)-DTBZ. Distribution volumes (V_T) and standardized uptake values (SUVs) were compared between groups. Three methods for calculation of non-displaceable uptake (V_ND) or reference SUV were applied: (1) use of [¹⁸F]FP-(+)-DTBZ reference V_T as V_ND, assuming V_ND is uniform across organs; (2) use of [¹⁸F]FP-(?)-DTBZ pancreatic V_T as V_ND, assuming that V_ND is uniform between enantiomers in the pancreas; and (3) use of a scaled [¹⁸F]FP-(+)-DTBZ reference V_T as V_ND, assuming that a ratio of non-displaceable uptake between organs is uniform between enantiomers. Group differences in V_T (or SUV), binding potential (BP_ND), or SUV ratio (SUVR) were estimated using these three methods.

Results

[¹⁸F]FP-(?)-DTBZ V_T values were different among organs, and V_T(+) and V_T(?) were also different in the renal cortex and spleen. Method 3 with the spleen to estimate V_ND (or reference SUV) gave the highest non-displaceable uptake and the largest HC vs. T1DM group differences. Significant group differences were also observed in V_T (or SUV) with method 1 using spleen. SUV was affected by differences in the input function between groups and between enantiomers.

Conclusions

Non-displaceable uptake was different among organs and between enantiomers. Use of scaled spleen V_T values for V_ND is a suitable method for quantification of VMAT2 in the pancreas.

     

Voxel-based NK1 Receptor Occupancy Measurements with [<Superscript>18</Superscript>F]SPA-RQ and Positron Emission Tomography: A Procedure for Assessing Errors from Image Reconstruction and Physiological Modeling

Purpose Receptor occupancy studies with positron emission tomography (PET) are widely used as aids in the drug development process. This study introduces a general procedure for assessing errors that arise from the applied image processing methods in PET receptor occupancy studies using the neurokinin-1 (NK1) receptor occupancy study as an example. Procedures The bias and variance among eight combinations of image reconstruction and model calculation methods for estimating voxel-level receptor occupancy results were examined. The tests were performed using a dynamic numerical phantom based on a previous PET drug occupancy study with the NK1 receptor antagonist tracer [¹⁸F]SPA-RQ. Results The simplified reference tissue model with basis functions (SRTM BF) was best at estimating receptor occupancy in terms of average bias. On the other hand, median root prior (MRP) image reconstruction produced the lowest variances in the occupancy estimates. These results suggest that SRTM BF and MRP is, in this case, the combination of choice in voxel-based receptor occupancy calculation. In the calculation of regional binding potential values, the commonly used sample mean is not applicable and, e.g., the median could be used instead. Conclusions This study shows that even this kind of complicated receptor study can be statistically evaluated. The reconstruction methods had an effect on the variance in the voxel-based receptor occupancy calculation. The model calculation methods influenced the average bias. The test method was found useful in assessing the methodological sources of systematic and random error in receptor occupancy estimation with PET.     

Assessing Glomerular Filtration in Small Animals Using [<Superscript>68</Superscript>Ga]DTPA and [<Superscript>68</Superscript>Ga]EDTA with PET Imaging

Purpose

Determining the glomerular filtration rate (GFR) is essential for clinical medicine but also for pre-clinical animal studies. Functional imaging using positron emission tomography (PET) allows repetitive almost non-invasive measurements. The aim of the study was the development and evaluation of easily synthesizable PET tracers for GFR measurements in small animals.

Procedures

Diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) were labeled with Ga-68. The binding to blood cells and plasma proteins was tested in vitro. The distribution of the tracers in rats was analyzed by PET imaging and ex vivo measurements. From the time-activity-curve of the blood compartment (heart) and the total tracer mass excreted by the kidney, the GFR was calculated. These values were compared directly with the inulin clearance in the same animals.

Results

Both tracers did not bind to blood cells. [⁶⁸Ga]DPTA but not [⁶⁸Ga]EDTA showed strong binding to plasma proteins. For this reason, [⁶⁸Ga]DPTA stayed much longer in the blood and only 30 % of the injected dose was eliminated by the kidney within 60 min whereas the excretion of [⁶⁸Ga]EDTA was 89 ± 1 %. The calculated GFR using [⁶⁸Ga]EDTA was comparable to the measured inulin clearance in the same animal. Using [⁶⁸Ga]-DPTA, the measurements led to values which were 80 % below the normal GFR. The results also revealed that definition of the volume of interest for the blood compartment affects the calculation and may lead to a slight overestimation of the GFR.

Conclusions

[⁶⁸Ga]EDTA is a suitable tracer for GFR calculation from PET imaging in small animals. It is easy to be labeled, and the results are in good accordance with the inulin clearance. [⁶⁸Ga]DTPA led to a marked underestimation of GFR due to its strong binding to plasma proteins and is therefore not an appropriate tracer for GFR measurements.

     

Radiochemical Synthesis,Rodent Biodistribution and Tumor Uptake,and Dosimetry Calculations of [<Superscript>11</Superscript>C] Methylated LY2181308

Purpose

The aim of the study was to develop a rapid and reproducible method to label LY2181308, an antisense oligonucleotide to Survivin, with carbon-11 in order to study its in vivo biodistribution and tumor uptake in rodents and its human dosimetry based on baboon data.

Methods

Randomly [¹¹C] methylated LY2181308 was produced with [¹¹C] methyl iodide. The biodistribution was performed in female Sprague–Dawley (SD) rats and EMT-6 tumor-bearing mice in the presence of nonradioactive LY2181308. Human dosimetry calculations were based on baboon PET studies.

Results

In SD rats, the kidney and liver were the organs with the most accumulation of radioactivity. Tumor uptake in mice was also relatively high after 5 min and remained constant for up to 1 h. Baboon dosimetry suggested that up to 42 mCi of radioactivity could be administered to human with a dose-limiting organ being the kidneys with a radiation dose of 32 µGy/MBq (0.118 rad/mCi).

Conclusions

[¹¹C] Methylated LY2181308 to rodents and baboons showed its biodistribution, tumor uptake, and human dosimetry evaluation. These results should facilitate the understanding of the pharmacokinetics of LY2181308 prior to use as a potential new therapeutic agent in oncology as well as to warrant more in vivo validations as a potentially useful tumor-imaging agent.

     

PET Imaging Analysis of Vitamin B<Subscript>1</Subscript> Kinetics with [<Superscript>11</Superscript>C]Thiamine and its Derivative [<Superscript>11</Superscript>C]Thiamine Tetrahydrofurfuryl Disulfide in Rats

Purpose

Thiamine is an essential component of glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is better absorbed than readily-available water-soluble thiamine salts because it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions have not yet been clarified. C-11-labeled thiamine and TTFD were recently synthesized by our group. In this study, to clarify the differences in pharmacokinetics and metabolism of these probes, a quantitative PET imaging study and radiometabolite analysis of C-11-labeled thiamine and TTFD were performed in the rat heart.

Procedures

Positron emission tomography (PET) imaging with [¹¹C]thiamine and [¹¹C]TTFD was performed in normal rats to determine the pharmacokinetics of these probes, and the radiometabolites of both probes from the blood and heart tissue were analyzed by thin-layer chromatography.

Results

Accumulation of [¹¹C]TTFD was significantly higher than that of [¹¹C]thiamine in the rat heart. Moreover, as a result of the radiometabolite analysis of heart tissue at 15 min after the injection of [¹¹C]TTFD, thiamine pyrophosphate, which serves as a cofactor for the enzymes involved in glucose metabolism, was found as the major radiometabolite and at a significantly higher level than in the [¹¹C]thiamine-injected group.

Conclusions

PET imaging techniques for visualizing the kinetics and metabolism of thiamine using [¹¹C]thiamine and [¹¹C]TTFD were developed in this study. Consequently, noninvasive PET imaging for the pathophysiology of thiamine-related cardiac function may provide novel information about heart failure and related disorders.

     

Evaluation of TSPO PET Ligands [<Superscript>18</Superscript>F]VUIIS1009A and [<Superscript>18</Superscript>F]VUIIS1009B: Tracers for Cancer Imaging

Purpose

Positron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [¹⁸F]VUIIS1009A ([¹⁸F]3A) and [¹⁸F]VUIIS1009B ([¹⁸F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats.

Procedures

VUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D ¹H-¹⁵N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [¹⁸F]VUIIS1009A and [¹⁸F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [¹⁸F]VUIIS1009A/B injections in glioma-bearing rats, with binding reversibility and specificity evaluated by radioligand displacement. In vivo radiometabolite analysis was performed using radio-TLC, and quantitative analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry.

Results

Both VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC₅₀ values against PK11195 approximately 500-fold lower than DPA-714. However, HSQC NMR suggested that VUIIS1009A and VUIIS1009B share a common binding pocket within mammalian TSPO (mTSPO) as DPA-714 and to a lesser extent, PK11195. [¹⁸F]VUIIS1009A ([¹⁸F]3A) and [¹⁸F]VUIIS1009B ([¹⁸F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [¹⁸F]VUIIS1009A and [¹⁸F]VUIIS1009B exhibited greater binding potential (k ₃/k ₄)in tumor tissue compared to [¹⁸F]DPA-714. Interestingly, [¹⁸F]VUIIS1009B exhibited significantly greater tumor uptake (V _T) than [¹⁸F]VUIIS1009A, which was attributed primarily to greater plasma-to-tumor extraction efficiency.

Conclusions

The novel PET ligand [¹⁸F]VUIIS1009B exhibits promising characteristics for imaging glioma; its superiority over [¹⁸F]VUIIS1009A, a regioisomer, appears to be primarily due to improved plasma extraction efficiency. Continued evaluation of [¹⁸F]VUIIS1009B as a high-affinity TSPO PET ligand for precision medicine appears warranted.

     

Investigation of cis-4-[<Superscript>18</Superscript>F]Fluoro-D-Proline Uptake in Human Brain Tumors After Multimodal Treatment

Purpose

Cis-4-[¹⁸F]fluoro-D-proline (D-cis-[¹⁸F]FPro) has been shown to pass the intact blood-brain barrier and to accumulate in areas of secondary neurodegeneration and necrosis in the rat brain while uptake in experimental brain tumors is low. This pilot study explores the uptake behavior of D-cis-[¹⁸F]FPro in human brain tumors after multimodal treatment.

Procedures

In a prospective study, 27 patients with suspected recurrent brain tumor after treatment with surgery, radiotherapy, and/or chemotherapy (SRC) were investigated by dynamic positron emission tomography (PET) using D-cis-[¹⁸F]FPro (22 high-grade gliomas, one unspecified glioma, and 4 metastases). Furthermore, two patients with untreated lesions were included (one glioblastoma, one reactive astrogliosis). Data were compared with the results of PET using O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET) which detects viable tumor tissue. Tracer distribution, mean and maximum lesion-to-brain ratios (LBR_mean, LBR_max), and time-to-peak (TTP) of the time activity curve (TAC) of tracer uptake were evaluated. Final diagnosis was determined by histology (n?=?9), clinical follow-up (n?=?10), or by [¹⁸F]FET PET (n?=?10).

Results

D-cis-[¹⁸F]FPro showed high uptake in both recurrent brain tumors (n?=?11) and lesions classified as treatment-related changes (TRC) only (n?=?16) (LBR_mean 2.2?±?0.7 and 2.1?±?0.6, n.s.; LBR_max 3.4?±?1.2 and 3.2?±?1.3, n.s.). The untreated glioblastoma and the lesion showing reactive astrogliosis exhibited low D-cis-[¹⁸F]FPro uptake. Distribution of [¹⁸F]FET and D-cis-[¹⁸F]FPro uptake was discordant in 21/29 cases indicating that the uptake mechanisms are different.

Conclusion

The high accumulation of D-cis-[¹⁸F]FPro in pretreated brain tumors and TRC supports the hypothesis that tracer uptake is related to cell death. Further studies before and after therapy are needed to assess the potential of D-cis-[¹⁸F]FPro for treatment monitoring.

     

N-[<Superscript>11</Superscript>C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs

Purpose

Chemokine receptor 4 (CXCR4) is overexpressed in many cancers and a potential drug target. We have recently developed the tracer N-[¹¹C]methyl-AMD3465 for imaging of CXCR4 expression by positron emission tomography (PET). We investigated the pharmacokinetics of N-[¹¹C]methyl-AMD3465 in rats bearing a C6 tumor and assessed whether the CXCR4 occupancy by the drug Plerixafor® can be measured with this PET tracer.

Procedure

A subcutaneous C6 tumor was grown in Wistar rats. Dynamic N-[¹¹C]methyl-AMD3465 PET scans with arterial blood sampling was performed in control rats and rats pretreated with Plerixafor® (30 mg/kg, s.c). The distribution volume (V _T) of the tracer was estimated by compartment modeling with a two-tissue reversible compartment model (2TRCM) and by Logan graphical analysis. The non-displaceable binding potential (BP_ND) was estimated with the 2TRCM. Next, CXCR4 receptor occupancy of different doses of the drug Plerixafor® (0.5–60 mg/kg) was investigated.

Results

The tumor could be clearly visualized by PET in control animals. Pretreatment with 30 mg/kg Plerixafor® significantly reduced tumor uptake (SUV 0.65 ± 0.08 vs. 0.20 ± 0.01, p < 0.05). N-[¹¹C]Methyl-AMD3465 was slowly metabolized in vivo, with 70 ± 7% of the tracer in plasma still being intact after 60 min. The tracer showed reversible in vivo binding to its receptor. Both 2TRCM modeling and Logan graphical analysis could be used to estimate V _T. Pre-treatment with 30 mg/kg Plerixafor® resulted in a significant reduction in V _T (2TCRM 0.87 ± 0.10 vs. 0.23 ± 0.12, p < 0.05) and BP_ND (1.85 ± 0.14 vs. 0.87 ± 0.12, p < 0.01). Receptor occupancy by Plerixafor® was dose-dependent with an in vivo ED₅₀ of 12.7 ± 4.0 mg/kg. Logan analysis gave comparable results.

Conclusion

N-[¹¹C]Methyl-AMD3465 PET can be used to visualize CXCR4 expression and to calculate receptor occupancy. V _T determined by Logan graphical analysis is a suitable parameter to assess CXCR4 receptor occupancy. This approach can easily be translated to humans and used for early drug development and optimization of drug dosing schedules.

     

<Superscript>11</Superscript>C-Acetate PET in the Evaluation of Brain Glioma: Comparison with <Superscript>11</Superscript>C-Methionine and <Superscript>18</Superscript>F-FDG-PET

PURPOSE: The aim of the study is to retrospectively investigate the usefulness of (11)C-acetate (ACE)-positron emission tomography (PET) for evaluation of brain glioma, in comparison with (11)C-methionine (MET) and 2-deoxy-2-(18)F-fluoro-D: -glucose (FDG). PROCEDURES: Fifteen patients with brain glioma referred to initial diagnosis were examined with ACE, MET, and FDG-PET. Five patients had low-grade gliomas (grade II), three had anaplastic astrocytomas (grade III), and seven had glioblastomas (grade IV). PET results were evaluated by visual and semiquantitative analysis. For semiquantitative analysis, the standardized uptake value (SUV) and tumor to contralateral normal gray matter (T/N) ratio were calculated. The sensitivity for detection of high-grade gliomas was calculated using visual analysis. RESULTS: Sensitivities of ACE, MET, and FDG were 90%, 100%, and 40%, respectively. ACE and MET T/N ratios were significantly higher than that of FDG. ACE and FDG SUV in high-grade gliomas were significantly higher than that in low-grade gliomas. No significant differences were observed using MET. CONCLUSIONS: ACE PET is a potentially useful radiotracer for detecting brain gliomas and differentiating high-grade gliomas.     

[<Superscript>11</Superscript>C] Acetoacetate Utilization by Breast and Prostate Tumors: a PET and Biodistribution Study in Mice

PURPOSE: A significant positive correlation has been observed between ketone body availability and their uptake by tumor cells. Our objective was to evaluate [11C]acetoacetate as a potential tracer of ketone body utilization by breast and prostate tumors and to compare it with [11C]acetate. METHODS: Biodistribution studies were performed with [11C]acetoacetate and [11C]acetate in mice bearing breast or prostate tumors. The percentage of the injected dose accumulated per gram of tissue was determined. These results were complemented by dynamic positron emission tomography (PET) imaging of the radiotracer uptake and dosimetry calculations. RESULTS: [11C]Acetoacetate uptake was optimal between 5 and 30 min, with maximal uptake of 2.72, 2.42, 2.54, and 2.19% injected dose (%ID)/g for MC7-L1, MC4-L2, PC3, and LN-CaP tumors respectively. Tumor retention for [11C]acetoacetate tended to be higher than [11C]acetate, but this did not reach statistical significance. [11C]Acetate uptake was reached within 15 min with optimal uptake of 1.25, 2.30, and 0.96%ID/g for MC7-L1, MC4-L2, and PC-3 tumors, respectively. CONCLUSIONS: We observed a moderate uptake of [11C]acetoacetate in breast and prostate tumors with low background activity due to rapid elimination of this tracer. Further studies are warranted to determine if this tracer can detect slow-growing breast and prostate cancers in the clinical setting.     

Radiation Dosimetry of a Novel Adenosine A<Subscript>2A</Subscript> Receptor Radioligand [<Superscript>11</Superscript>C]Preladenant Based on PET/CT Imaging and Ex Vivo Biodistribution in Rats

Purpose

[¹¹C]Preladenant was developed as a novel adenosine A_2A receptor PET radioligand. The aim of this study was to determine the radiation dosimetry of [¹¹C]preladenant and to investigate whether dosimetry estimation based on organ harvesting can be replaced by positron emission tomography (PET)/x-ray computed tomography (CT) imaging in rats.

Procedures

Male Wistar rats (n?=?35) were i.v. injected with [¹¹C]preladenant. The tracer biodistribution was determined by organ harvesting at 1, 5, 15, 30, 60, and 90 min post injection. Hollow organs including the stomach, intestines, and urinary bladder were harvested with contents. In 10 rats, a 90-min dynamic PET/CT scan of the torso was acquired. Twenty volumes of interest (VOIs) were manually drawn on the PET image using the CT image of the same animal as anatomical reference. The dynamic time-activity curves were used to calculate organ residence times (RTs). Human radiation dosimetry estimates, derived from rat data, were calculated with OLINDA/EXM 1.1.

Results

PET-imaging and organ-harvesting estimated comparable organ RTs, with differences of 6–27 %, except for the lungs, pancreas, and urinary bladder, with differences of 48, 53, and 60, respectively. The critical organ was the small intestine with a dose of 25 μSv/MBq. The effective doses (EDs) calculated from imaging-based and organ-harvesting-derived data were 5.5 and 5.6 μSv/MBq, respectively, using the International Commission on Radiological Protection 60 tissue weighting factors.

Conclusions

The ED of [¹¹C]preladenant (2 mSv for a 370-MBq injected dose) is comparable with other C-11-labeled PET tracers. Estimation of the radiation dosimetry of [¹¹C]preladenant by PET/CT imaging in rats is feasible and gives comparable results to organ harvesting, provided that small VOIs are used and the content of hollow organs is taken into account. Dosimetry by PET imaging can strongly reduce the number of laboratory animals required.

     

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.