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.

     

Imaging Characteristics and First Experience of [<Superscript>68</Superscript>Ga]THP-PSMA,a Novel Probe for Rapid Kit-Based Ga-68 Labeling and PET Imaging: Comparative Analysis with [<Superscript>68</Superscript>Ga]PSMA I&amp;T

Purpose

[⁶⁸Ga]Trishydroxypyridinone (THP)–prostate-specific membrane antigen (PSMA) is a novel tracer that can be labeled in one step by cold reconstitution of a kit with unprocessed generator eluate, targeting PSMA via the lysine-urea-glutamate (KuE) motif. The aim of this study was to evaluate the human imaging characteristics of [⁶⁸Ga]THP-PSMA.

Procedures

[⁶⁸Ga]THP-PSMA positron emission tomography (PET)/x-ray computed tomography (CT) was performed in 25 patients with biochemical recurrence after radical prostatectomy for prostate cancer. Urinary and biliary excretion and tumor lesion uptake were quantified using standardized uptake values (SUVs). Imaging characteristics were assessed in terms of non-target organ uptake, background activity, target-to-background ratios (TBRs) of tumor lesions, and frequency of bladder halo artifacts. Findings were compared to a matched cohort of 25 patients undergoing PET/CT with the established agent [⁶⁸Ga]PSMA I&T.

Results

Physiologic uptake of [⁶⁸Ga]THP-PSMA was significantly lower in salivary glands (P?<?0.0001), liver (P?<?0.0001), spleen (P?<?0.0001), and kidneys (P?<?0.0001) than with [⁶⁸Ga]PSMA I&T. While biliary tracer excretion of [⁶⁸Ga]THP-PSMA was negligible, urinary tracer excretion of [⁶⁸Ga]THP-PSMA was fast, and significantly higher than for [⁶⁸Ga]PSMA I&T, contributing to a higher frequency of bladder artifacts. Malignant lesion uptake of [⁶⁸Ga]THP-PSMA assessed as either SUV or TBR was significantly lower than with [⁶⁸Ga]PSMA I&T.

Conclusion

[⁶⁸Ga]THP-PSMA yields suitable in vivo uptake characteristics. The simplified synthesis method for [⁶⁸Ga]THP-PSMA may facilitate wider application and higher patient throughput with PSMA imaging. However, direct intraindividual comparison studies are needed to assess the relative performance of [⁶⁸Ga]THP-PSMA vs other PSMA ligands in terms of clinical detection rate and image quality.

     

A Feasibility Study Showing [<Superscript>68</Superscript>Ga]Citrate PET Detects Prostate Cancer

Purpose

The management of advanced or recurrent prostate cancer is limited in part by the lack of effective imaging agents. Metabolic changes in prostate cancer have previously been exploited for imaging, culminating in the recent US FDA approval of [¹¹C]choline for the detection of subclinical recurrent disease after definitive local therapy. Despite this milestone, production of [¹¹C]choline requires an on-site cyclotron, limiting the scope of medical centers at which this scan can be offered. In this pilot study, we tested whether prostate cancer could be imaged with positron emission tomography (PET) using [⁶⁸Ga]citrate, a radiotracer that targets iron metabolism but is produced without a cyclotron.

Procedures

Eight patients with castrate-resistant prostate cancer were enrolled in this single-center feasibility study. All patients had evidence of metastatic disease by standard of care imaging [X-ray computed tomography (CT), bone scan, or magnetic resonance imaging (MRI)] prior to PET with [⁶⁸Ga]citrate. Patients were intravenously injected with increasing doses of [⁶⁸Ga]citrate (136.9 to a maximum of 259 MBq). Uptake time was steadily increased from 1 h to approximately 3.5 h for the final 4 patients, and all patients were imaged with a PET/MRI. Qualitative and semi-quantitative (maximum standardized uptake value (SUV_max)) assessment of the metastatic lesions was performed and compared to the standard of care imaging.

Results

At 1- and 2-h imaging times post injection, there were no detectable lesions with [⁶⁸Ga]citrate PET. At 3- to 4-h uptake time, there were a total of 71 [⁶⁸Ga]citrate-positive lesions (67 osseous, 1 liver, and 3 lymph node). Of these, 65 lesions were visible on the standard of care imaging (CT and/or bone scan). One PET-avid osseous vertebral body metastasis was not apparent on either CT or bone scan. Twenty-five lesions were not PET-avid but seen on CT and bone scan (17 bone, 6 lymph node, 1 pleural, and 1 liver). The average of the maximum SUVs for bone or soft tissue metastases for patients treated at higher doses and uptake time was statistically higher than the corresponding parameter in normal liver, muscle, and bone. Visually obvious blood pool activity was observed even 3–4 h post injection, suggesting that further optimization of the [⁶⁸Ga]citrate imaging protocol is required to maximize signal-to-background ratios.

Conclusions

Our preliminary results support that PET with [⁶⁸Ga]citrate may be a novel tool for imaging prostate cancer. Future studies are needed to determine the optimal imaging protocol, the clinical significance of [⁶⁸Ga]citrate uptake, and its role in therapeutic decisions.

     

Improving PET Quantification of Small Animal [<Superscript>68</Superscript>Ga]DOTA-Labeled PET/CT Studies by Using a CT-Based Positron Range Correction

Purpose

Image quality of positron emission tomography (PET) tracers that emits high-energy positrons, such as Ga-68, Rb-82, or I-124, is significantly affected by positron range (PR) effects. PR effects are especially important in small animal PET studies, since they can limit spatial resolution and quantitative accuracy of the images. Since generators accessibility has made Ga-68 tracers wide available, the aim of this study is to show how the quantitative results of [⁶⁸Ga]DOTA-labeled PET/X-ray computed tomography (CT) imaging of neuroendocrine tumors in mice can be improved using positron range correction (PRC).

Procedures

Eighteen scans in 12 mice were evaluated, with three different models of tumors: PC12, AR42J, and meningiomas. In addition, three different [⁶⁸Ga]DOTA-labeled radiotracers were used to evaluate the PRC with different tracer distributions: [⁶⁸Ga]DOTANOC, [⁶⁸Ga]DOTATOC, and [⁶⁸Ga]DOTATATE. Two PRC methods were evaluated: a tissue-dependent (TD-PRC) and a tissue-dependent spatially-variant correction (TDSV-PRC). Taking a region in the liver as reference, the tissue-to-liver ratio values for tumor tissue (TLR_tumor), lung (TLR_lung), and necrotic areas within the tumors (TLR_necrotic) and their respective relative variations (ΔTLR) were evaluated.

Results

All TLR values in the PRC images were significantly different (p?<?0.05) than the ones from non-PRC images. The relative differences of the tumor TLR values, respect to the case with no PRC, were ΔTLR_tumor 87?±?41 % (TD-PRC) and 85?±?46 % (TDSV-PRC). TLR_lung decreased when applying PRC, being this effect more remarkable for the TDSV-PRC method, with relative differences respect to no PRC: ΔTLR_lung?=???45?±?24 (TD-PRC), ??55?±?18 (TDSV-PRC). TLR_necrotic values also decreased when using PRC, with more noticeable differences for TD-PRC: ΔTLR_necrotic?=???52?±?6 (TD-PRC), ??48?±?8 (TDSV-PRC).

Conclusion

The PRC methods proposed provide a significant quantitative improvement in [⁶⁸Ga]DOTA-labeled PET/CT imaging of mice with neuroendocrine tumors, hence demonstrating that these techniques could also ameliorate the deleterious effect of the positron range in clinical PET imaging.

     

Repeatability of [<Superscript>68</Superscript>Ga]DKFZ11-PSMA PET Scans for Detecting Prostate-specific Membrane Antigen-positive Prostate Cancer

Purpose

We studied the effect of varying specific activity of [⁶⁸Ga]DKFZ-PSMA11 ([⁶⁸Ga]DP11) on repeated imaging of prostate-specific membrane antigen-positive (PSMA+) xenograft tumors.

Procedures

Athymic nude mice bearing PC3-PIP (PSMA+) and PC3 (PSMA?) bilateral flank tumors were assessed to study intra- and inter-day repeatability of [⁶⁸Ga]DP11 imaging in mice administered [⁶⁸Ga]DP11 or [⁶⁷Ga]DP11 (as a dilution tracer) using imaging and biodistribution studies.

Results

Region of interest (ROI) analysis of the [⁶⁸Ga]DP11 imaging study indicated that the uptake was constant on the same day or consecutive days. Prior imaging with [⁶⁸Ga]DP11 did not significantly influence the subsequent uptake of [⁶⁸Ga]DP11. Uptake of [⁶⁸Ga]DP11 (60 min) and [⁶⁷Ga]DP11 (24 h) in PC3-PIP tumors was 12.37 ± 4.19 %ID/g and 12.49 ± 6.88 %ID/g, respectively; [⁶⁸Ga]DP11 was 13.83 ± 3.77 and 17.76 ± 1.84 on same-day and 15.98 ± 5.82 %ID/g on second-day imaging.

Conclusions

This study demonstrates that [⁶⁸Ga]DP11, in a given PSMA+ lesion, is constant under several same-day or serial-day imaging conditions.

     

[<Superscript>18</Superscript>F]Fluorocholine PET/CT Imaging of Liver Cancer: Radiopathologic Correlation with Tissue Phospholipid Profiling

Purpose

[¹⁸F]fluorocholine PET/CT can detect hepatocellular carcinoma (HCC) based on imaging the initial steps of phosphatidylcholine synthesis. To relate the diagnostic performance of [¹⁸F]fluorocholine positron emission tomography (PET)/x-ray computed tomography (CT) to the phospholipid composition of liver tumors, radiopathologic correspondence was performed in patients with early-stage liver cancer who had undergone [¹⁸F]fluorocholine PET/CT before tumor resection.

Procedures

Tumor and adjacent liver were profiled by liquid chromatography mass spectrometry, quantifying phosphatidylcholine species by mass-to-charge ratio. For clinical-radiopathologic correlation, HCC profiles were reduced to two orthogonal principal component factors (PCF1 and PCF2) accounting for 80 % of total profile variation.

Results

Tissues from 31 HCC patients and 4 intrahepatic cholangiocarcinoma (ICC) patients were analyzed, revealing significantly higher levels of phosphocholine, CDP-choline, and highly saturated phosphatidylcholine species in HCC tumors relative to adjacent liver and ICC tumors. Significant loading values for PCF1 corresponded to phosphatidylcholines containing poly-unsaturated fatty acids while PCF2 corresponded only to highly saturated phosphatidylcholines. Only PCF2 correlated significantly with HCC tumor-to-liver [¹⁸F]fluorocholine uptake ratio (ρ = 0.59, p < 0.0005). Sensitivity for all tumors based on an abnormal [¹⁸F]fluorocholine uptake ratio was 93 % while sensitivity for HCC based on increased tumor [¹⁸F]fluorocholine uptake was 84 %, with lower levels of highly saturated phosphatidylcholines in tumors showing low [¹⁸F]fluorocholine uptake.

Conclusion

Most HCC tumors contain high levels of saturated phosphatidylcholines, supporting their dependence on de novo fatty acid metabolism for phospholipid membrane synthesis. While [¹⁸F]fluorocholine PET/CT can serve to identify these lipogenic tumors, its imperfect diagnostic sensitivity implies metabolic heterogeneity across HCC and a weaker lipogenic phenotype in some tumors.

     

Development and Evaluation of User-Friendly Single Vial DOTA-Peptide Kit Formulations,Specifically Designed for Radiolabelling with <Superscript>68</Superscript>Ga from a Tin Dioxide <Superscript>68</Superscript>Ge/<Superscript>68</Superscript>Ga Generator

Purpose

This study was aimed to develop single vial 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide kits to be used with fractionated eluates from a SnO₂-based ⁶⁸Ge/⁶⁸Ga generator.

Procedures

Kits were formulated with 35 μg DOTA-Tyr³-Thre⁸-octreotide, DOTA-[Tyr³]-octreotide and DOTA-[NaI³]-octreotide (DOTATATE, DOTATOC and DOTANOC) and sodium acetate powder, vacuum-dried and stored at ?20 °C for up to 12 months. Labelling of the kits was carried out with 2 ml ⁶⁸Ga eluate. Comparative labelling was carried out using aqueous DOTA-peptide stock solutions kept frozen at ?20 °C for up to 12 months.

Results

The quality of the kits was found to be suitable over a 1-year storage period (pH, sterility, endotoxin content, radiolabelling efficiency and radiochemical yields of ⁶⁸Ga-labelled DOTA-peptides). Radiochemical yields ranged from 73 to 83 %, while those obtained from stock solutions from 64 to 79 %. No significant decline in kit labelling yields was observed over a 12-month storage period.

Conclusion

The single vial kit formulations met the quality release specifications for human administration and appear to be highly advantageous over using peptide stock solutions in terms of stability and user-friendliness.

     

Clinical Translation of [68Ga]Ga-NOTA-anti-MMR-sdAb for PET/CT Imaging of Protumorigenic Macrophages

Molecular Imaging and Biology - Macrophage mannose receptor (MMR, CD206) expressing tumor-associated macrophages (TAM) are&nbsp;protumorigenic and was reported to negatively impact therapy...     

Tumor Targeting <Emphasis Type="Italic">via</Emphasis> Sialic Acid: [<Superscript>68</Superscript>Ga]DOTA-en-pba as a New Tool for Molecular Imaging of Cancer with PET

Purpose

The aim of this study was to demonstrate the potential of Ga-68-labeled macrocycle (DOTA-en-pba) conjugated with phenylboronic vector for tumor recognition by positron emission tomography (PET), based on targeting of the overexpressed sialic acid (Sia).

Procedures

The imaging reporter DOTA-en-pba was synthesized and labeled with Ga-68 at high efficiency. Cell binding assay on Mel-C and B16-F10 melanoma cells was used to evaluate melanin production and Sia overexpression to determine the best model for demonstrating the capability of [⁶⁸Ga]DOTA-en-pba to recognize tumors. The in vivo PET imaging was done with B16-F10 tumor-bearing SCID mice injected with [⁶⁸Ga]DOTA-en-pba intravenously. Tumor, blood, and urine metabolites were assessed to evaluate the presence of a targeting agent.

Results

The affinity of [⁶⁸Ga]DOTA-en-pba to Sia was demonstrated on B16-F10 melanoma cells, after the production of melanin as well as Sia overexpression was proved to be up to four times higher in this cell line compared to that in Mel-C cells. Biodistribution studies in B16-F10 tumor-bearing SCID mice showed blood clearance at the time points studied, while uptake in the tumor peaked at 60 min post-injection (6.36?±?2.41 % ID/g). The acquired PET images were in accordance with the ex vivo biodistribution results. Metabolite assessment on tumor, blood, and urine samples showed that [⁶⁸Ga]DOTA-en-pba remains unmetabolized up to at least 60 min post-injection.

Conclusions

Our work is the first attempt for in vivo imaging of cancer by targeting overexpression of sialic acid on cancer cells with a radiotracer in PET.

     

The Effect of Defective PET Detectors in Clinical Simultaneous [<Superscript>18</Superscript>F]FDG Time-of-Flight PET/MR Imaging

Purpose

The purpose of this study was to evaluate the effect of defective positron emission tomography (PET) detectors on clinical PET image quality in simultaneous PET/magnetic resonance imaging (MRI) for both time-of-flight (TOF) and non-TOF reconstructed images.

Procedures

A total of six patients with various malignant tumors were included and underwent a 2-deoxy-2-[¹⁸F]fluoro-d-glucose PET scan in a fully functional simultaneous TOF PET/MRI. TOF and non-TOF PET images were reconstructed before and after simulating defective detector units. All images were clinically assessed and scored. In addition, a quantitative assessment was performed. Differences were ascertained and compared using the Wilcoxon matched pairs signed-rank test.

Results

Without TOF, the image artifacts introduced by one defective detector unit already started to degrade the overall image quality. It reduced the confidence and could lead to a change in diagnosis. Simulating three or five defective detector units resulted in more artifacts and further reduced overall image quality and confidence. By including TOF information, the effects were mitigated: Images reconstructed with one defective detector unit had similar scores as the ones without defective units. The average absolute percentage error for one, three, and five defective detector units were respectively 8, 20, and 37 % for the non-TOF cases and only 5, 11, and 19 % for the TOF cases.

Conclusion

Our study indicates that PET image artifacts due to (simulated) defective detectors are significantly mitigated with the integration of TOF information in simultaneous PET/MR. One defective detector unit introduces, on average, a 5 % absolute percentage error. However, in TOF imaging, even in cases with one or three defective units for head and neck imaging and one defective unit for chest and abdominal imaging, overall image quality, artifact scoring, and reader confidence are not significantly degraded.

     

PSMA-Based [<Superscript>18</Superscript>F]DCFPyL PET/CT Is Superior to Conventional Imaging for Lesion Detection in Patients with Metastatic Prostate Cancer

Purpose

Current standard of care conventional imaging modalities (CIM) such as X-ray computed tomography (CT) and bone scan can be limited for detection of metastatic prostate cancer and therefore improved imaging methods are an unmet clinical need. We evaluated the utility of a novel second-generation low molecular weight radiofluorinated prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) radiotracer, [¹⁸F]DCFPyL, in patients with metastatic prostate cancer.

Procedures

Nine patients with suspected prostate cancer recurrence, eight with CIM evidence of metastatic prostate cancer and one with biochemical recurrence, were imaged with [¹⁸F]DCFPyL PET/CT. Eight of the patients had contemporaneous CIM for comparison. A lesion-by-lesion comparison of the detection of suspected sites of metastatic prostate cancer was carried out between PET and CIM. Statistical analysis for estimated proportions of inter-modality agreement for detection of metastatic disease was calculated accounting for intra-patient correlation using general estimating equation (GEE) intercept-only regression models.

Results

One hundred thirty-nine sites of PET positive [¹⁸F]DCFPyL uptake (138 definite, 1 equivocal) for metastatic disease were detected in the eight patients with available comparison CIM. By contrast, only 45 lesions were identified on CIM (30 definite, 15 equivocal). When lesions were negative or equivocal on CIM, it was estimated that a large portion of these lesions or 0.72 (95 % confidence interval (CI) 0.55–0.84) would be positive on [¹⁸F]DCFPyL PET. Conversely, of those lesions negative or equivocal on [¹⁸F]DCFPyL PET, it was estimated that only a very small proportion or 0.03 (95 % CI 0.01–0.07) would be positive on CIM. Delayed 2-h-post-injection time point PET yielded higher tumor radiotracer uptake and higher tumor-to-background ratios than an earlier 1-h-post-injection time point.

Conclusions

A novel PSMA-targeted PET radiotracer, [¹⁸F]DCFPyL, was able to a large number of suspected sites of prostate cancer, many of which were occult or equivocal by CIM. This study provides strong preliminary evidence for the use of this second-generation PSMA-targeted PET radiotracer for detection of metastatic prostate cancer and lends further support for the importance of PSMA-targeted PET imaging in prostate cancer.

     

A Comparison of [<Superscript>99m</Superscript>Tc]Duramycin and [<Superscript>99m</Superscript>Tc]Annexin V in SPECT/CT Imaging Atherosclerotic Plaques

Purpose

Apoptosis is a key factor in unstable plaques. The aim of this study is to evaluate the utility of visualizing atherosclerotic plaques with radiolabeled duramycin and Annexin V.

Procedures

ApoE^?/? mice were fed with a high-fat diet to develop atherosclerosis, C57 mice as a control. Using a routine conjugation protocol, highly pure [^99mTc]duramycin and [^99mTc]Annexin V were obtained, which were applied for in vitro cell assays of apoptosis and in vivo imaging of atherosclerotic plaques in the animal model. Oil Red O staining, TUNEL, hematoxylin-eosin (HE), and CD68 immunostaining were used to evaluate the deposition of lipids and presence of apoptotic macrophages in the lesions where focal intensity positively correlated with the uptake of both tracers.

Results

[^99mTc]duramycin and [^99mTc]Annexin V with a high radiochemical purity (97.13 ± 1.52 and 94.94 ± 0.65 %, respectively) and a well stability at room temperature were used. Apoptotic cells binding activity to [^99mTc]duramycin (Kd, 6.92 nM and Bmax, 56.04 mol/10¹⁹ cells) was significantly greater than [^99mTc]Annexin V (Kd, 12.63 nM and Bmax, 31.55 mol/10¹⁹ cells). Compared with [^99mTc]Annexin V, [^99mTc]duramycin bound avidly to atherosclerotic lesions with a higher plaque-to-background ratio (P/B was 8.23 ± 0.91 and 5.45 ± 0.48 at 20 weeks, 15.02 ± 0.23 and 12.14 ± 0.22 at 30 weeks). No plaques were found in C57 control mice. Furthermore, Oil Red O staining showed lipid deposition areas were significantly increased in ApoE^?/? mice at 20 and 30 weeks, and TUNEL and CD68 staining confirmed that the focal uptake of both tracers contained abundant apoptotic macrophages.

Conclusions

This stable, fast clearing, and highly specific [^99mTc]duramycin, therefore, can be useful for the quantification of vulnerable atherosclerotic plaques.

     

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.

     

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.

     

PET Imaging of Human Brown Adipose Tissue with the TSPO Tracer [<Superscript>11</Superscript>C]PBR28

Purpose

Brown adipose tissue (BAT) in adult humans has been recently rediscovered and intensively investigated as a new potential therapeutic target for obesity and type 2 diabetes (T2D). However, reliable assessment of BAT mass in vivo represents a considerable challenge. The purpose of this investigation is to demonstrate for the first time that human BAT depots can be imaged with a translocator protein (TSPO)-specific positron emission tomography (PET) tracer [¹¹C]PBR28 under thermoneutral conditions.

Procedures

In this retrospective analysis, we analyzed the images of three healthy volunteers who underwent PET/magnetic resonance (MR) imaging after injection of 14 m Ci of [¹¹C]PBR28 at room temperature. Thirty-minute static PET images were reconstructed from the data obtained 60–90 min after the injection of the tracer.

Results

[¹¹C]PBR28 uptake in the neck/supraclavicular regions was identified, which was parallel to the known distribution pattern of human BAT depots. These areas co-localized with the areas of hyperintensity and corresponded to fat on T1-weighted MR images. Standardized uptake value (SUV) was used to quantify [¹¹C]PBR28 signal in BAT depots. The average (± SD) SUV_(mean) and SUV_max for BAT depots was 2.13 (± 0.33) and 3.19 (± 0.34), respectively, while the average SUV_(mean) for muscle and subcutaneous adipose tissue was 0.79 (± 0.1) and 0.18 (± 0.04), respectively.

Conclusions

In this brief article, we provide the first evidence suggesting that [¹¹C]PBR28, a widely available TSPO-specific PET tracer, can be used for imaging human BAT mass under thermoneutral conditions.

     

[<Superscript>18</Superscript>F]DPA-714 PET Imaging Reveals Global Neuroinflammation in Zika Virus-Infected Mice

Purpose

The association of Zika virus (ZIKV) infection and development of neurological sequelae require a better understanding of the pathogenic mechanisms causing severe disease. The purpose of this study was to evaluate the ability and sensitivity of positron emission tomography (PET) imaging using [¹⁸F]DPA-714, a translocator protein (TSPO) 18 kDa radioligand, to detect and quantify neuroinflammation in ZIKV-infected mice.

Procedures

We assessed ZIKV-induced pathogenesis in wild-type C57BL/6 mice administered an antibody to inhibit type I interferon (IFN) signaling. [¹⁸F]DPA-714 PET imaging was performed on days 3, 6, and 10 post-infection (PI), and tissues were subsequently processed for histological evaluation, quantification of microgliosis, and detection of viral RNA by in situ hybridization (ISH).

Results

In susceptible ZIKV-infected mice, viral titers in the brain increased from days 3 to 10 PI. Over this span, these mice showed a two- to sixfold increase in global brain neuroinflammation using [¹⁸F]DPA-714 PET imaging despite limited, regional detection of viral RNA. No measurable increase in ionized calcium binding adaptor molecule 1 (Iba-1) expression was noted at day 3 PI; however, there was a modest increase at day 6 PI and an approximately significant fourfold increase in Iba-1 expression at day 10 PI in the susceptible ZIKV-infected group relative to controls.

Conclusions

The results of the current study demonstrate that global neuroinflammation plays a significant role in the progression of ZIKV infection and that [¹⁸F]DPA-714 PET imaging is a sensitive tool relative to histology for the detection of neuroinflammation. [¹⁸F]DPA-714 PET imaging may be useful in dynamically characterizing the pathology associated with neurotropic viruses and the evaluation of therapeutics being developed for treatment of infectious diseases.

     

[<Superscript>68</Superscript>Ga]PSMA-HBED-CC Uptake in Osteolytic,Osteoblastic, and Bone Marrow Metastases of Prostate Cancer Patients

Purpose

The aim of this study was to evaluate potential differences in “Glu-NH-CO-NH-Lys” radio-labeled with [⁶⁸Ga]gallium N,N-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N-diacetic acid ([⁶⁸Ga]PSMA-HBED-CC) uptake in osteolytic, osteoblastic, mixed, and bone marrow metastases in prostate cancer (PC) patients.

Procedures

This retrospective study was approved by the local ethics committee. Patients who received [⁶⁸Ga]PSMA-HBED-CC positron emission tomography/computed tomography ([⁶⁸Ga]PSMA-PET/CT) with at least one positive bone metastasis were included in this study. Only patients who have not received systemic therapy for their PC were included. Bone metastases had to be confirmed by at least one other imaging modality or follow-up investigation. The maximum standardized uptake value (SUV_max) and mean Hounsfield units (HU_mean) of each metastasis were measured. Based on CT, each metastasis was classified as osteolytic (OL), osteoblastic (OB), bone marrow (BM), or mixed (M).

Results

One hundred fifty-four bone metastases in 30 patients were evaluated. Eighty out of 154 (51.9%) metastases were classified as OB, 21/154 (13.6%) as OL, 23/154 (14.9%) as M, and 30/154 (19.5%) as BM. The SUV_max for the different types of metastases were 10.6 ± 7.07 (OB), 24.0 ± 19.3 (OL), 16.0 ± 21.0 (M), and 14.7 ± 9.9 (BM). The SUV_max of OB vs. OL and OB vs. BM metastases differed significantly (p ≤ 0.025). A significant negative correlation between HU_mean and SUV_max (r = ?0.23, p < 0.05) was measured.

Conclusions

[⁶⁸Ga]PSMA-HBED-CC uptake is higher in osteolytic and bone marrow metastases compared to osteoblastic metastases. Information derived from [⁶⁸Ga]PSMA-PET and CT complement each other for the reliable diagnosis of the different types of bone metastases in PC patients.

     

On the Significance of Defective Block Detectors in Clinical <Superscript>18</Superscript>F-FDG PET/CT Imaging

Introduction  

Clinical positron emission tomography (PET) systems based on block detector designs suffer occasional block detector failures, which can result in patient scan cancelations. In this study, we examine the effect of defective block detectors on measurements of maximum standard uptake value (SUV_max) and clinical image quality in 3D 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) PET/computed tomography (CT) imaging.     

Myeloperoxidase Activity Imaging Using <Superscript>67</Superscript>Ga Labeled Substrate

Purpose The aim of the study is to assess the feasibility of imaging specific activity of myeloperoxidase (MPO), a leukocyte enzyme with important roles in inflammation and atherosclerosis, by single photon emission computed tomography (SPECT) using a novel ⁶⁷Ga-labeled radiotracer obtained by conjugating desferrioxamine (DF) and hydroxyindolyl acetic acid in vivo. Materials and Methods A reducing substrate of MPO (I) was synthesized by reacting commercially available DF with 2-(5-hydroxy-1H-indol-3-yl) acetic acid in the presence of a coupling agent [dicyclohexyl carbodiimide (DCC)]. The chelating unit was labeled with ⁶⁷Ga, and its interaction with MPO was characterized using MALDI-TOF and UV–vis. Mice with Matrigel implants containing human MPO were used to model diseased tissues rich in MPO. Three hours after the injection of ⁶⁷Ga–I, SPECT/computed tomography (CT) imaging was performed on a high-resolution Gamma Medica X-SPECT system. Biodistribution studies were performed six hours after the injection of the radiotracer. Results The feasibility of compound I oligomerization in the presence of MPO and MPO-mediated cross-linking with proteins was initially confirmed in vitro. In vivo, a 2.7-fold increase in target-to-muscle ratio could be measured in MPO-containing Matrigel implants in mice. Biodistribution experiments demonstrated a 60% increase of radioactivity in MPO-containing vs. control (contralateral) Matrigel implants. Conclusion ⁶⁷Ga–I can be used to image MPO activity in a model system. The accumulation mechanism is based on a differential pharmacokinetics because of the size increase resulting from ⁶⁷Ga–I interaction with the target enzyme. M. Querol and J. W. Chen contributed equally to this work.