Molecular Imaging Techniques to Study the Biodistribution of Orally Administered <Superscript>99m</Superscript>Tc-Labelled Naive and Ligand-Tagged Nanoparticles

Purpose  

Study by molecular imaging the biodistribution of poly(anhydride) nanoparticles after oral administration.     

Synthesis and Biological Evaluation of Cyclic [<Superscript>99m</Superscript>Tc]-HYNIC-CGPRPPC as a Fibrin-Binding Peptide for Molecular Imaging of Thrombosis and Its Comparison with [<Superscript>99m</Superscript>Tc]-HYNIC-GPRPP

Purpose

Many patients worldwide suffer from cardiovascular diseases for which an underlying factor is thrombosis. Devising a molecular imaging technique for early detection of thrombosis in a clinical setting is highly recommended. Because fibrin is a major constituent of clots and is present in all types of thrombi but absent in circulation, it is a highly specific and sensitive target for molecular imaging of thrombi. It is assumed that cyclization of peptides will improve the receptor binding affinity and stability of the peptide. In the present study, we have developed linear and cyclic fibrin-binding peptides for thrombus imaging and compared their biological properties.

Procedures

Linear HYNIC-GPRPP and cyclic HYNIC-CGPRPPC peptides were synthesized using a standard Fmoc strategy and radiolabeled with Tc-99m. The stability of the radiolabeled peptides in human plasma and their affinity for fibrin and blood clots were determined. Blood clearance and biodistribution were evaluated in rats and mice, respectively. The peptide with the highest affinity was injected to a live rabbit femoral thrombosis model, and scintigraphic images were obtained.

Results

In vitro studies show that peptides are stable in human plasma and have a high affinity for human fibrin. They also demonstrated fast blood clearance in rats and high thrombus uptake in the Balb/c mice femoral thrombosis model. Femoral thrombosis was visualized 30 min postinjection of cyclic peptide in a live rabbit model using single photon emission computed tomography (SPECT)/X-ray computed tomography.

Conclusions

The results indicate that the cyclic peptide is a promising agent for molecular imaging of fibrin using SPECT.

     

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.

     

Imaging CXCR4 Expression with <Superscript>99m</Superscript>Tc-Radiolabeled Small-Interference RNA in Experimental Human Breast Cancer Xenografts

Purpose

Noninvasive quantification of chemokine receptor 4 (CXCR4) expression could serve as a prognostic indicator and may be of value for the design of personalized therapies and posttreatment monitoring. The objective of the present study was to assess the use of ^99mTc-radiolabeled small-interference RNA (siRNA) targeting CXCR4 to detect CXCR4 expression in vivo.

Procedures

CXCR4 siRNAs were radiolabeled with ^99mTc using the bifunctional chelator hydrazinonicotinamide (HYNIC), and the labeling efficiency, specific activity and radiochemical purity were determined. The stability of the probe in serum was assessed by measuring its radiochemical purity and inhibitory activity by RT-PCR and western blotting. Biodistribution studies and static imaging were performed in MDA-MB-231 tumor-bearing mice.

Results

Radiochemical purity remained highly stable in PBS and fresh human serum at room temperature and at 37 °C. Radiolabeled siRNA1 showed strong inhibitory effects similar to those of unlabeled siRNA1 on both CXCR4 messenger RNA (mRNA) and protein in vitro. The excretion of the probe occurred mainly through the liver and kidneys. Tumors were clearly visualized at 1–10 h after injection of the probe, but not after injection of the control probe.

Conclusions

^99mTc-labeled CXCR4 siRNA1 shows tumor-specific accumulation and could be a promising strategy for the visualization of CXCR4 expression in human breast cancer.

     

SPECT Imaging with <Superscript>99m</Superscript>Tc-Labeled EGFR-Specific Nanobody for <Emphasis Type="Italic">In Vivo</Emphasis> Monitoring of EGFR Expression

Purpose

Overexpression of the epidermal growth factor receptor (EGFR) occurs with high incidence in various carcinomas. The oncogenic expression of the receptor has been exploited for immunoglobulin-based diagnostics and therapeutics. We describe the use of a llama single-domain antibody fragment, termed Nanobody®, for the in vivo radioimmunodetection of EGFR overexpressing tumors using single photon emission computed tomography (SPECT) in mice.

Methods

Fluorescence-activated cell sorting (FACS) analysis was performed to evaluate the specificity and selectivity of 8B6 Nanobody to bind EGFR on EGFR overexpressing cells. The Nanobody was then labeled with ^99mTc via its C-terminal histidine tail. Uptake in normal organs and tissues was assessed by ex vivo analysis. In vivo tumor targeting of ^99mTc-8B6 Nanobody was evaluated via pinhole SPECT in mice bearing xenografts of tumor cells with either high (A431) or moderate (DU145) overexpression of EGFR.

Results

FACS analysis indicated that the 8B6 Nanobody only recognizes cells overexpressing EGFR. In vivo blood clearance of ^99mTc-8B6 Nanobody is relatively fast (half-life, 1.5 h) and mainly via the kidneys. At 3 h postinjection, total kidney accumulation is high (46.6?±?0.9%IA) compared to total liver uptake (18.9?±?0.6%IA). Pinhole SPECT imaging of mice bearing A431 xenografts showed higher average tumor uptake (5.2?±?0.5%IA/cm³) of ^99mTc-8B6 Nanobody compared to DU145 xenografts (1.8?±?0.3%IA/cm³, p?

Conclusion

The EGFR-binding Nanobody investigated in this study shows high specificity and selectivity towards EGFR overexpressing cells. Pinhole SPECT analysis with ^99mTc-8B6 Nanobody enabled in vivo discrimination between tumors with high and moderate EGFR overexpression. The favorable biodistribution further corroborates the suitability of Nanobodies for in vivo tumor imaging.

     

Influence of Glioma's Multidrug Resistance Phenotype on <Superscript>99m</Superscript>Tc-Tetrofosmin Uptake

Purpose  

Multidrug resistance (MDR) remains a major obstacle to successful chemotherapeutic treatment of cancer. Several chemotherapeutic and radiopharmaceutical agents are substrates of the pumps encoded by the MDR genes, and therefore, their accumulation is prevented. We evaluated in vivo whether [^99mTc]tetrofosmin (^99mTc-TF) uptake is influenced by the MDR profile of gliomas.     

The Synthesis of <Superscript>18</Superscript>F-FDS and Its Potential Application in Molecular Imaging

Purpose 2-Deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) is the most commonly used positron emission tomography (PET) tracer for oncological and neurological imaging, but it has limitations on detecting tumor or inflammation in brain gray matter. In this study, we describe the development of 2-deoxy-2-[¹⁸F]fluorosorbitol (¹⁸F-FDS) and its possible application in lesion detection around brain area. Procedures ¹⁸F-FDS was obtained by reduction of FDG using NaBH₄ (81 ± 4% yield in 30 min). Cell uptake/efflux experiments in cell culture and small animal PET imaging on tumor and inflammation models were performed. Results Despite the low accumulation in cell culture, ¹⁸F-FDS had good tumor uptake and contrast in the subcutaneous U87MG tumor model (4.54%ID/g at 30 min post-injection). Minimal uptake in the normal mouse brain facilitated good tumor contrast in both U87MG and GL-26 orthotopic tumor models. ¹⁸F-FDS also had increased uptake in the inflamed foci of the TPA-induced acute inflammation model. Conclusions Because of the ease of synthesis and favorable in vivo kinetics, ¹⁸F-FDS may have potential applications in certain cases where FDG is inadequate (e.g., brain tumor). Zi-Bo Li and Zhanhong Wu contributed equally to this work     

Synthesis and Optimization of the Labeling Procedure of <Superscript>99m</Superscript>Tc-Hynic-Interleukin-2 for <Emphasis Type=Italic>In vivo</Emphasis> Imaging of Activated T lymphocytes

Introduction  

We have previously described the labeling of interleukin-2 (IL2) with ¹²³I and ^99mTc-N₃S. Both radiopharmaceuticals were successfully applied in humans to image several inflammatory lesions and autoimmune diseases characterized by tissue infiltrating lymphocytes expressing the IL2 receptor (CD25). However, both radiopharmaceuticals had some specific disadvantages, such as cost and time of synthesis.     

Involvement of Nigrostriatal Pathway in Japanese Encephalitis with Movement Disorders: Evidence from <Superscript>99m</Superscript>Tc-TRODAT-1 and <Superscript>123</Superscript>I-IBZM SPECT Imagings

Purpose  

The purpose of this study was to evaluate molecular evidence of nigrostriatal pathway involvement in Japanese encephalitis (JE) survivors with movement complications.     

Impact of CT attenuation correction on the viability pattern assessed by <Superscript>99m</Superscript>Tc-tetrofosmin SPECT/<Superscript>18</Superscript>F-FDG PET

SPECT myocardial perfusion imaging (MPI) is commonly used for comprehensive interpretation of metabolic PET FDG imaging in ischemic dysfunctional myocardium. We evaluated the difference in scan interpretation introduced by CT attenuation correction (CTAC) of SPECT MPI in patients undergoing viability characterization by ^99mTc SPECT MPI/PET FDG. In 46 consecutive patients (mean age 64, range 36–83 years) with dysfunctional myocardium, we analyzed viability from combined SPECT MPI and PET FDG scanning without attenuation correction (NC) and with CTAC for SPECT MPI. FDG uptake was classified in groups of percent uptake using the segment with maximum tracer in SPECT perfusion uptake as reference. Viability patterns were categorized as normal, mismatch, mild match and scar by relative comparison of SPECT and PET. Applying CTAC introduced a different reference segment for the normalization of PET FDG study in 57% of cases. As a result, the flow-metabolism pattern changed in 28% of segments, yielding a normal, mismatch, mild match and scar pattern in 462, 150, 123, and 47 segments with NC and 553, 86, 108, and 35 with CTAC, respectively (P = 0.001). Thus, by introducing CTAC for SPECT MPI 25% of segments originally classified as scar were reclassified and the number of normal segments increased by 20%. Introducing CTAC decreased by 54% the number of patients with possible indication for revascularization, from 26/46 to 12/46 (P < 0.001). Different interpretation of myocardial viability can be observed when using CTAC instead of NC SPECT MPI as reference for PET FDG scans.     

Non-Invasive Imaging of Amyloid Deposits in a Mouse Model of AGel Using <Superscript>99m</Superscript>Tc-Modified Nanobodies and SPECT/CT

Purpose

Gelsolin amyloidosis (AGel), also known as familial amyloidosis, Finnish type (FAF), is an autosomal, dominant, incurable disease caused by a point mutation (G654A/T) in the gelsolin (GSN) gene. The mutation results in loss of a Ca²⁺-binding site in the second gelsolin domain. Subsequent incorrect folding exposes a cryptic furin cleavage site, leading to the formation of a 68-kDa C-terminal cleavage product (C68) in the trans-Golgi network. This C68 fragment is cleaved by membrane type 1-matrix metalloproteinase (MT1-MMP) during secretion into the extracellular environment, releasing 8- and 5-kDa amyloidogenic peptides. These peptides aggregate and cause disease-associated symptoms. We set out to investigate whether AGel-specific nanobodies could be used to monitor amyloidogenic gelsolin buildup.

Procedures

Three nanobodies (FAF Nb1–3) raised against the 8-kDa fragment were screened as AGel amyloid imaging agents in WT and AGel mice using ^99mTc-based single-photon emission computed tomography (SPECT)/X-ray tomography (CT), biodistribution analysis, and immunofluorescence (IF). The quantitative characteristics were analyzed in a follow-up study with a Nb11-expressing mouse model.

Results

All three nanobodies possess the characteristics desired for a ^99mTc-based SPECT/CT imaging agent, high specificity and a low background signal. FAF Nb1 was identified as the most potent, based on its superior signal-to-noise ratio and signal specificity. As a proof of concept, we implemented ^99mTc-FAF Nb1 in a follow-up study of the Nb11-expressing AGel mouse model. Using biodistribution analysis and immunofluorescence, we demonstrated the validity of the data acquired via ^99mTc-FAF Nb1 SPECT/CT.

Conclusion

These findings demonstrate the potential of this nanobody as a non-invasive tool to image amyloidogenic gelsolin deposition and assess the therapeutic capacity of AGel therapeutics currently under development. We propose that this approach can be extended to other amyloid diseases, thereby contributing to the development of specific therapies.

     

Evaluation of [<Superscript>99m</Superscript>Tc]Radiolabeled Macrophage Mannose Receptor-Specific Nanobodies for Targeting of Atherosclerotic Lesions in Mice

Purpose

Macrophage accumulation characterizes the development of atherosclerotic plaques, and the presence of certain macrophage subsets might be an indicator of plaque phenotype and (in)stability. The macrophage mannose receptor (MMR) is expressed on alternatively activated macrophages and found at sites of intraplaque hemorrhage and neovascularization. It has been proposed as target to identify vulnerable plaques. Therefore, we aimed to assess the feasibility of using anti-MMR nanobodies (Nbs) as molecular tracers for nuclear imaging in an animal model of atherosclerosis.

Procedure

Anti-MMR and control Nb, radiolabeled with Tc-99m, were injected in ApoE^?/? and/or C57Bl/6 mice (n = 6). In vivo competition studies involving pre-injection of excess of unlabeled anti-MMR Nb (n = 3) and injection of anti-MMR Nb in MMR^?/? mice (n = 3) were performed to demonstrate specificity. At 3 h p.i. radioactive uptake in organs, tissues and aorta segments were evaluated. Autoradiography and immunofluorescence were performed on aortic sections.

Results

Significantly higher uptake was observed in all aortic segments of ApoE^?/? mice injected with anti-MMR Nb compared to control Nb (1.36 ± 0.67 vs 0.38 ± 0.13 percent of injected dose per gram (%ID/g), p ≤ 0.001). Surprisingly, high aortic uptake was also observed in C57Bl/6 mice (1.50 ± 0.43%ID/g, p ≥ 0.05 compared to ApoE^?/?), while aortic uptake was reduced to background levels in the case of competition and in MMR^?/? mice (0.46 ± 0.10 and 0.22 ± 0.06%ID/g, respectively; p ≤ 0.001). Therefore, expression of MMR along healthy aortas was suggested. Autoradiography showed no specific radioactive signal within atherosclerotic plaques, but rather localization of the signal along the aorta, correlating with MMR expression in perivascular tissue as demonstrated by immunofluorescence.

Conclusions

No significant uptake of MMR-specific Nb could be observed in atherosclerotic lesions of ApoE^?/? mice in this study. A specific perivascular signal causing a non-negligible background level was demonstrated. This observation should be considered when using MMR as a target in molecular imaging of atherosclerosis, as well as use of translational animal models with vulnerable plaques.

     

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.     

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.

     

Impact of Nonhybrid <Superscript>99m</Superscript>Tc-MDP-SPECT/CT Image Fusion in Diagnostic and Treatment of Oromaxillofacial Malignancies

Purpose  

The aim of this study was to prospectively investigate the clinical impact of image fusion of computed tomography (CT) and single photon emission computed tomography (SPECT) diagnostics in head and neck cancer adjacent or fixed to bony maxillofacial structures.     

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.

     

Parametric Imaging of [<Superscript>11</Superscript>C]Flumazenil Binding in the Rat Brain

Purpose

This study evaluates the performance of several parametric methods for assessing [¹¹C]flumazenil binding distribution in the rat brain.

Procedures

Dynamic (60 min) positron emission tomography data with metabolite-corrected plasma input function were retrospectively analyzed (male Wistar rats, n = 10). Distribution volume (V _T) images were generated from basis function method (BFM), Logan graphical analysis (Logan), and spectral analysis (SA). Using the pons as pseudo-reference tissue, binding potential (BP _ND and DVR–1) images were obtained from receptor parametric imaging algorithms (RPM and SRTM2) and reference Logan (RLogan). Standardized uptake value images (SUV and SUVR) were also computed for different intervals post-injection. Next, regional averages were extracted from the parametric images, using pre-defined volumes of interest, which were also applied to the regional time-activity curves from the dynamic data. Parametric data were compared to their regional counterparts and to two-tissue compartment model (2TCM)-based values (previously defined as the model of choice for rats). Parameter agreement was assessed by linear regression analysis and Bland-Altman plots.

Results

All parametric methods strongly correlated to their regional counterparts (R ² > 0.97) and to the 2TCM values (R ² ≥ 0.95). SA and RLogan underestimated V _T and BP _ND (slope of 0.93 and 0.86, respectively), while SUVR-1 overestimated BP _ND (slope higher than 1.07 for all intervals). While BFM and SRTM2 had the smallest bias to 2TCM values (0.05 for both), ratio Bland-Altman plots showed Logan and RLogan displayed relative errors which were comparable between different regions, in contrast with the other methods. Although SUV consistently underestimated V _T, the bias in this method was also constant across regions.

Conclusions

All parametric methods performed well for the analysis of [¹¹C]flumazenil distribution and binding in the rat brain. However, Logan and RLogan slightly outperformed the other methods in terms of precision, providing robust parameter estimation and constant bias. Yet, other methods can be of interest, because they can provide tissue perfusion (i.e., K ₁ with BFM and SA), relative flow (i.e., R ₁ with RPM and SRTM2), and model order (SA) images.

     

Clinical utility of <Superscript>18</Superscript>F-FDG positron emission tomography/computed tomography scan vs. <Superscript>99m</Superscript>Tc-HMPAO white blood cell single-photon emission computed tomography in extra-cardiac work-up of infective endocarditis

The extra-cardiac work-up in infective endocarditis (IE) comprises a search for primary and secondary infective foci. Whether ¹⁸FDG-PET/CT or WBC-SPECT/CT is superior in detection of clinically relevant extra-cardiac manifestations in IE is unexplored. The objectives of this study were to identify the numbers of positive findings detected by each imaging modality, to evaluate the clinical relevance of these findings and to define the reproducibility for extra-cardiac foci in patients with definite IE. Each modality was evaluated for numbers and location of positive extra-cardiac foci in patients with definite IE. A team of 2?×?2 cardiologists evaluated each finding to determine clinical relevance. Clinical utility was determined by 4 criteria converted into an ordinal scale. Using the manifestation with highest clinical utility rating in each patient, the clinical impact of the two imaging modalities was expressed in a clinical utility score. To evaluate reproducibility for each modality, an imaging core laboratory reviewed all findings. In 55 IE patients, 91 pathological foci were found by FDG-PET/CT and 37 foci were identified by WBC-SPECT/CT (p?<?0.001). The clinical utility of FDG-PET/CT was significantly higher than that of WBC-SPECT/CT when comparing clinical utility score (2.06 vs. 1.17; p?=?0.01). In assessment of extra-cardiac diagnostics in IE, inter-observer reproducibility was substantial for WBC-SPECT/CT (k 0.69, 95% CI 0.49–0.89) and substantial to excellent for FDG-PET/CT (k 0.79, 95% CI 0.61–0.98). FDG-PET/CT has a significantly higher clinical utility score than WBC SPECT/CT and is potentially superior to WBC-SPECT/CT in detection of extra-cardiac pathology in patients with IE.     

A Noninvasive [<Superscript>99m</Superscript>Tc]DTPA SPECT/CT Imaging Methodology as a Measure of Lung Permeability in a Guinea Pig Model of COPD

Purpose  

The purposes of this study are (1) to develop an efficient aerosol inhalation system for the delivery of [^99mTc]DTPA aerosol into guinea pig airways with high uniformity for measuring lung clearance using SPECT/CT imaging, as a measure of lung permeability, and (2) to use [^99mTc]DTPA studies in guinea pig model of chronic obstructive pulmonary disease (COPD) to determine its usefulness in studying pathogenesis of COPD.