Comparison of [18F]-Tracers in Various Experimental Tumor Models by PET Imaging and Identification of an Early Response Biomarker for the Novel Microtubule Stabilizer Patupilone

Purpose  The suitability of [¹⁸F]FDG, [¹⁸F]FLT, [¹⁸F]FET, and [¹⁸F]FCH as non-invasive positron emission tomography (PET) biomarkers for monitoring response to chemotherapy was analyzed in various experimental tumor models. Procedures  Tracer uptake into three syngeneic rodent tumor models and ten human xenograft models was evaluated using semiquantitative analysis of small-animal PET data. Murine RIF-1 fibrosarcomas and [¹⁸F]FLT were selected to monitor the effects of the novel cytotoxic patupilone. Results  Except [¹⁸F]FCH, all tracers provided good tumor visualization. Highest [¹⁸F]FDG uptake was identified in syngeneic tumors. Xenograft models, however, showed low [¹⁸F]FDG SUVs and were better visualized by [¹⁸F]FLT. Monitoring the effects of patupilone on [¹⁸F]FLT uptake in RIF-1 tumors revealed a significant decrease of tracer uptake after 24 h, which strongly negatively correlated with apoptosis. Conclusion  [¹⁸F]FLT PET of experimental tumors is a viable complement to [¹⁸F]FDG for preclinical drug development. [¹⁸F]FLT may be an excellent biomarker for patupilone-induced apoptosis. T. Ebenhan and M. Honer contributed equally to this work. An erratum to this article can be found at     

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.     

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.     

Quantitative imaging of myocardial infarct in rats with high resolution pinhole SPECT

Small animal imaging of cardiovascular disease using single photon emission tomography (SPECT) can be used to provide quantitative measurements of myocardial infarct. The purpose of this study was to demonstrate the accuracy of pinhole SPECT imaging with [^99mTc]sestamibi for estimation of infarct size in a rat model of coronary artery disease. Nine rats had their left anterior descending artery ligated to induce a region of myocardial infarct. These animals were injected with 37 MBq [^99mTc]sestamibi, and, 1 h later, scanned on a pinhole SPECT system for 30 min. The defect size measured with SPECT, which was dependent on a threshold applied to the short axis circumferential profiles, was compared against the gold standard triphenyltetrazolium chloride (TTC) staining. The size of the perfusion deficit measured using [^99mTc]sestamibi SPECT compared very favorably with the TTC staining result, for threshold values in the range 50–70%. The optimum threshold was approximately 70%, giving an excellent correlation (R ²=0.89, p<0.001). Estimation of infarct size by [^99mTc] sestamibi SPECT yielded an excellent agreement with TTC staining. In conclusion, measurement of myocardial infarct with SPECT can be used to study the rat heart in vivo, and provides a quantitative measure of myocardial viability.     

First Evaluation of [11C]R116301 as an In Vivo Tracer of NK1 Receptors in Man

Purpose  NK1 receptors have been implicated in various neuropsychiatric and other disorders. R116301 is a selective NK1 receptor antagonist. In this pilot study, [¹¹C]R116301 was evaluated as a potential positron emission tomography (PET) ligand for the NK1 receptor. Procedures  Two dynamic PET studies were performed in three normal volunteers before and after a blocking dose of aprepitant. Data were analyzed using striatum to cerebellum standardized uptake value (SUV) ratios. Results  Baseline SUV ratios at 60–90 min after injection ranged from 1.22 to 1.70. Following aprepitant administration, this specific signal was completely blocked. Aprepitant administration did not significantly affect uptake in cerebellum, confirming the absence of NK1 receptors in cerebellum. Conclusion  These preliminary results indicate that [¹¹C]R116301 has potential as a radioligand for in vivo assessment of NK1 receptors in the human brain.     

Transcranial Sonography and I-FP-CIT Single Photon Emission Computed Tomography in Movement Disorders

Diagnosis of Parkinson's disease (PD) can be difficult in the early stages of the disease. The aim of the study described here was to assess the correlation between transcranial sonography (TCS) and ¹²³I-FP-CIT ([¹²³I]ioflupane, N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-[¹²³I]iodophenyl)nortropane) SPECT (single photon emission computed tomography) findings and the diagnosis of PD. A total of 49 patients were enrolled in the study: 29 patients with PD, 7 patients with other parkinsonian syndromes, 11 patients with essential tremor and 2 with psychogenic movement disorder. Substantia nigra echogenicity was measured using TCS. SPECT was performed using DaTSCAN ([¹²³I]ioflupane). TCS and SPECT findings were correlated in 84% of patients, with κ = 0.62 (95% confidence interval: 0.38–0.86). TCS-measured substantia nigra echogenicity and SPECT-measured striatal binding ratio were negatively correlated (r = –0.326, p = 0.003). TCS/SPECT sensitivity, specificity and positive and negative predictive values for the diagnosis of PD were 89.7%/96.6%, 60.0%/70.0%, 76.5%/82.4% and 80.0%/93.3%, respectively. Both positive TCS and SPECT findings correlated significantly with the diagnosis of PD (κ = 0.52, 95% confidence interval: 0.27–0.76, and κ = 0.69, 95% confidence interval: 0.49–0.90, respectively).     

Pulmonary clearance of [99mTc]DTPA and [99mTc]albumin in smokers

We measured the pulmonary clearance of [^99mTc]DTPA and [^99mTc]albumin for 3 h in 10 non-smokers and 10 healthy smokers. Seven of the non-smokers had a monoexponential clearance of [^99mTc]DTPA with a mean half-life of 66±18 min. The other three had a biexponential clearance of [^99mTc]DTPA with a fraction of radioactivity clearing rapidly (f_F) of 14±4%. Eight smokers had biexponential clearance of [^99mTc]DTPA. The half-life of the fast and slow clearance components was 1265 and 62611 min respectively. The f_F was 56±25%. Two of the smokers showed a monoexponential clearance of [^99mTc]DTPA with a half-life of 72 and 55 min. All non-smokers had monoexponential clearance curves for [^99mTc]albumin, compared with seven smokers. The half-life was 279±43 min in non-smokers and 236±64 min in smokers. The difference in half-life was not significant. In three smokers, the clearance curves of [^99mTc]albumin were significantly better described by a bi-exponential equation. The f_F was 22±9%. The effects of smoking on the clearance of [^99mTc]albumin appear to be qualitatively similar to those on the clearance of [^99mTc]DTPA. Clearance of [^99mTc]albumin seems less sensitive to the effects of smoking than clearance of [^99mTc]DTPA.     

GRP Receptor Imaging of Prostate Cancer Using [99mTc]Demobesin 4: a First-in-Man Study

Purpose

We explored the imaging of bombesin receptors and evaluated the clinical use of [^99mTc]Demobesin 4 ([^99mTc]DB4) in prostate cancer patients.

Procedures

[^99mTc]DB4 was prepared according to Good Manufacturing Practice. Patients with prostate cancer underwent serial planar and SPECT imaging up to 3 h after administration. Blood and urine samples were taken to assess pharmacokinetics.

Results

[^99mTc]DB4 is safe and clears rapidly from the bloodstream via the kidneys resulting in low background activity. The tracer binds strongly to the gastrin-releasing peptide receptor (GRPR) in vivo as indicated by the high uptake in the pancreas seen in all patients. In patients who had undergone hormone therapy, [^99mTc]DB4 did not efficiently image metastatic prostate cancer. In contrast, in newly diagnosed patients local disease was visualised.

Conclusions

The GRPR is an unsuitable target for imaging refractory prostate cancer but may be useful in untreated disease. [^99mTc]DB4 is a promising radiopharmaceutical which merits further exploration in this specific group of patients.     

Technetium-99m-labelled HL91 and technetium-99m-labelled MIBI SPECT imaging for the detection of ischaemic viable myocardium: a preliminary study

Purpose: The assessment of myocardial viability has become an important aspect of the diagnostic and prognostic work‐up of patients with coronary artery disease. Technetium‐99m labelled sestamibi (^99mTc‐MIBI) myocardial perfusion imaging may underestimate the viability of ischaemic myocardium. Technetium‐99m labelled 4,9‐diaza‐3,3,10,10‐tetramethyldodecan‐2,11‐dione dioxime (^99mTc‐HL91) is a hypoxia‐avid agent which can identify acutely ischaemic viable myocardium in a canine model using a standard gamma camera. The aim of this study was to evaluate uptake character of ischaemic viable myocardium and diagnostic performance of single‐photon emission computed tomography (SPECT) imaging by ^99mTc‐HL91 and ^99mTc‐MIBI in detecting ischaemic viable myocardium in coronary heart disease. Methods: A total of 41 patients with coronary artery disease were recruited from March 2008 to May 2009. For detecting ischaemic viable myocardium, SPECT imaging by ^99mTc‐HL91 and ^99mTc‐MIBI were performed in all patients before coronary revascularization. Six patients with single ischaemic myocardial segment received a 2‐day SEPCT/CT imaging protocol and the uptake of ^99mTc‐HL91 in ischaemic myocardium was quantitatively analysed. The remaining 35 patients received a 1‐day ^99mTc‐HL91 and ^99mTc‐MIBI SPECT imaging protocol. Resting ^99mTc‐MIBI myocardial perfusion imaging in 3–18 months after revascularization was used as the standard methodology to evaluate the myocardial viability. Results: In 41 patients, 66 ischaemic myocardial segments were proven to be viable and 12 to be necrotic by resting ^99mTc‐MIBI myocardial perfusion imaging after coronary revascularization. Furthermore, 60 viable segments with negative uptake of ^99mTc‐MIBI showed positive uptake of ^99mTc‐HL91. The remaining six viable segments and 12 necrotic segments showed both negative uptake of ^99mTc‐HL91 and ^99mTc‐MIBI. The sensitivity, specificity, accuracy, Younden Index, positive predictive value and negative predictive value for evaluating ischaemic viable myocardium were 90·9%, 100%, 92·3%, 90·9%, 100% and 66·7%, respectively. Ischaemic viable myocardium had the negative ^99mTc‐MIBI uptake and positive ^99mTc‐HL91 uptake, which demonstrated a mismatched uptake character. Quantitative analysis indicated the uptake of ^99mTc‐HL91 in viable myocardium was increasing in the first 1–3 h and remained stable at the 3–4 h after injection. Conclusion: Functional SPECT imaging with ^99mTc‐HL91 and ^99mTc‐MIBI can be used to detect the seriously ischaemic but viable myocardium with a mismatched uptake character. The uptake of ^99mTc‐HL91 in the viable myocardium reached a stable level at 3–4 h after injection.     

Imaging VEGF Receptors and α<Subscript>v</Subscript>β<Subscript>3</Subscript> Integrins in a Mouse Hindlimb Ischemia Model of Peripheral Arterial Disease

Purpose

To compare targeted imaging of vascular endothelial growth factor (VEGF) receptors vs. α_vβ₃ integrins in a mouse hindlimb ischemia model of peripheral artery disease.

Procedures

Male wild-type (WT) C57BL/6 mice (8- to 10-week old) (n?=?24) underwent left femoral artery ligation. The right leg served as control. Five days later, mice were injected with either VEGF receptor targeting [^99mTc]DOTA-PEG-scVEGF ([^99mTc]scV) (n?=?8) or with α_vβ₃-targeting tracer [^99mTc]HYNIC-cycloRGD ([^99mTc]RGD) (n?=?8) and underwent single photon emission computed tomography (SPECT) x-ray computed tomography imaging. To assess non-specific [^99mTc]scV uptake, six additional mice received a mixture of [^99mTc]scV and 30-fold excess of targeting protein, scVEGF. Tracer uptake as %ID was measured using volumetric regions encompassing the hindlimb muscles and as %ID/g from harvested limb muscles. Double and triple immunofluorescent analysis on tissue sections established localization of α_vβ₃, VEGFR-1, VEGFR-2, as well as certain cell lineage markers.

Results

Tracer uptake, as %ID/g, was higher in ligated limbs of mice injected with [^99mTc]scV compared to ligated hindlimbs in mice injected with [^99mTc]RGD (p?=?0.02). The ratio of tracer uptake for ligated/control hindlimb was borderline higher for [^99mTc]scV than for [^99mTc]RGD (p?=?0.06). Immunofluorescent analysis showed higher prevalence of VEGFR-1, VEGFR-2, and α_vβ₃, in damaged vs. undamaged hindlimb tissue, but with little co-localization of these markers. Double immunofluorescent staining showed partial co-localization of VEGFR-1, VEGFR-2, and α_vβ_3, with endothelial cell marker FVIII, but not with CD31. Immunostaining for VEGFR-1 and VEGFR-2 additionally co-localized with lineage markers for endothelial progenitor cell and monocytes/macrophages, with a more diverse pattern of co-localization for VEGFR-2.

Conclusion

In a mouse hindlimb ischemia model of peripheral artery disease, [^99mTc]scV SPECT tracer-targeting VEGF receptors showed a more robust signal than [^99mTc]RGD tracer-targeting α_vβ₃. Immunofluorescent analysis suggests that uptake of [^99mTc]scV and [^99mTc]RGD in damaged tissue is due to non-overlapping cell populations and reflects different dynamic processes and that enhanced uptake of [^99mTc]scV may be due to the presence of VEGF receptors on additional cell types.

     

99Tcm-TRODAT-1多巴胺转运蛋白SPECT脑显像在亚临床期和临床期帕金森病模型猴诊断中的研究

目的探讨99Tcm-TRODAT-1多巴胺转运蛋白SPECT脑显像在帕金森病亚临床期诊断中的价值.方法对4只食蟹猴静脉注射多巴胺转运蛋白显像剂99Tcm-TRODAT-1,观察99Tcm-TRODAT-1在不同时间点正常猴体内分布并进行纹状体DAT功能分析.用MPTP分别制备无症状亚临床期和临床期PD猴模型,利用计算机感兴趣区(ROI)技术进行纹状体DAT功能半定量分析.结果99Tcm-TRODAT-1最佳SPECT脑显像时间为注射99Tcm-TRODAT-1后3～4 h.PD猴毁损侧(右侧)纹状体在亚临床期就已存在DAT功能的降低,并随着损伤的加重毁损侧纹状体DAT功能进一步降低,对侧纹状体的DAT也受损.结论99Tcm-TRODAT-1 SPECT脑显像可用于PD的亚临床期诊断和病情监测.     

Rapid hepatic clearance of 99mTc‐TMEOP: a new candidate for myocardial perfusion imaging

Background

^99mTc labeled radiotracers used in clinical practice lack the perfect characteristics for myocardial perfusion imaging. In particular, the high liver uptake can interfere in the interpretation of the inferior myocardial wall. Within the tricarbonyl approach, we used tris(pyrazolyl)methane ^99mTc organometallic complexes as a lead structure. Herein we present the production, in vivo and in vitro metabolic studies in rats and the first in vivo biodistribution in rats for tri‐methoxy‐tris‐pyrazolyl‐^99mTc‐(CO)₃ (^99mTc‐TMEOP), compared with ^99mTc‐sestamibi and ^99mTc‐tetrofosmin.

Methods

The chemical identity of ^99mTc‐TMEOP was characterized by RP‐HPLC. The octanol–water partition coefficient was determined under physiological conditions. In vitro stability and protein binding were determined using RP‐HPLC. In vivo stability was determined in blood, heart, liver and kidney homogenates, intestine and urine using RP‐HPLC. In vivo biodistribution was determined using dynamic planar acquisitions. Pinhole gated SPECT images were performed in other animals. Cardiac, liver and lung uptake were expressed as differential uptake ratios by drawing regions of interest in the organs of interest and around the total body. Heart–liver and heart–lung ratios were derived. Cardiac uptake was also expressed as percentage of injected activity. SPECT images were processed to determine the heart–liver ratio on SPECT images, to compare functional parameters between different tracers and to visualize homogeneous intracardiac tracer distribution.

Results

^99mTc‐TMEOP is a moderately lipophilic cation, is stable and does not undergo any transformation in vitro. ^99mTc‐TMEOP also shows a high in vivo stability. In vivo imaging shows liver kinetics faster than those of ^99mTc‐sestamibi and ^99mTc‐tetrofosmin. Cardiac uptake and functional analysis of pinhole gated SPECT data are comparable to those of ^99mTc‐sestamibi and ^99mTc‐tetrofosmin.

Conclusion

Although ^99mTc‐TMEOP shows a cardiac uptake between those of ^99mTc‐sestamibi and ^99mTc‐tetrofosmin, a better heart–liver ratio is obtained due to the faster liver washout. These results suggest possible faster cardiac perfusion imaging using ^99mTc‐TMEOP without liver activity interference. Copyright © 2010 John Wiley & Sons, Ltd.     

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.

     

In vivo evaluation of the dopaminergic neurotransmission system using [123I]FP‐CIT SPECT in 6‐OHDA lesioned rats

The 6‐hydroxydopamine (6‐OHDA) rodent model of Parkinson's disease (PD) has been used to evaluate the nigrostriatal pathway. The aim of this work was to explore the relationship between the degree of 6‐OHDA‐induced dopaminergic degeneration and [¹²³I]FP‐CIT binding using single photon emission computed tomography (SPECT). Fourteen rats received a 6‐OHDA injection (4 or 8 µg) into the left medial forebrain bundle. After 3 weeks, magnetic resonance imaging and scans with a small‐animal SPECT system were performed. Finally, the nigrostriatal lesion was assessed by immunohistochemical analysis. Immunohistochemical analysis confirmed two levels of dopaminergic degeneration. Lesions induced by 6‐OHDA diminished the ipsilateral [¹²³I]FP‐CIT binding by 61 and 76%, respectively. The decrease in tracer uptake between control and lesioned animals was statistically significant, as was the difference between the two 6‐OHDA lesioned groups. Results concluded that [¹²³I]FP‐CIT SPECT is a useful technique to discriminate the degree of dopaminergic degeneration in a rat model of PD. Copyright © 2014 John Wiley & Sons, Ltd.     

Localization of Deoxyglucose and Annexin A5 in Experimental Atheroma Correlates with Macrophage Infiltration but not Lipid Deposition in the Lesion

Purpose  

The aim of this study was to understand the relationship of lipid deposition to the macrophage content, macrophage metabolism, and apoptosis in plaque. We compared the uptake of 2-deoxy-2-fluoro-D-[¹⁴C]glucose ([¹⁴C]FDG) and [^99mTc]HYNIC-annexin V ([^99mTc]annexin A5) with the lesion histology in apolipoprotein E knockout (apoE^−/−) mice.     

Spatial Inhomogeneity of Cardiac Norepinephrine Transport Protein and Meta-[123I]Iodobenzylguanidine Uptake in Swine Myocardial Tissue

Purpose

The aim of the present study was to evaluate the expression of the cardiac norepinephrine transporter (NET) in the left ventricle (LV) of healthy pigs and its relationship with regional meta-[¹²³I]iodobenzylguanidine ([¹²³I]MIBG) myocardial uptake.

Procedures

Experiments were performed on animals injected with [¹²³I]MIBG and acquired 2 h later using an ultrafast CZT gamma camera to assess the regional myocardial uptake. After image acquisition, animals were euthanized; the heart was quickly excised and underwent to an ex vivo single photon emission tomography (SPECT) imaging. Four small samples of tissue were then harvested from mid-walls and apex of the left ventricle; NET densities were evaluated and further normalized for protein loading per cardiac region.

Results

Three variants of NET protein with different molecular weights were detected. The expression of NET was not homogenous in the LV, with the highest density in the inferior wall and the lowest one in the apical area. The regional in vivo [¹²³I]MIBG uptake revealed an analogous trend, showing a good linear relationship with NET expression. Parallel results were obtained from the ex vivo study.

Conclusion

This study elucidates the expression of three different variants of NET proteins into the left ventricular myocardium of a healthy pig. NET expression into the LV was not homogeneous and paralleled by differences in regional [¹²³I]MIBG uptake. Moreover, the correlation and the agreement between measurements of regional expression of NET variants and [¹²³I]MIBG uptake represent a relevant finding for inferences about NET expression in the context of clinical imaging.

     

Limitations of Small Animal PET Imaging with [18F]FDDNP and FDG for Quantitative Studies in a Transgenic Mouse Model of Alzheimer’s Disease

Purpose  We evaluated the usefulness of small animal brain positron emission tomography (PET) imaging with the amyloid-beta (Aβ) probe 2-(1-{6-[(2-[¹⁸F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malonitrile ([¹⁸F]FDDNP) and with 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) for detection and quantification of pathological changes occurring in a transgenic mouse model of Alzheimer’s disease (Tg2576 mice). Procedures  [¹⁸F]FDDNP (n = 6) and FDG-PET scans (n = 3) were recorded in Tg2576 mice (age 13–15 months) and age-matched wild-type litter mates. Brain volumes of interest were defined by co-registration of PET images with a 3D MOBY digital mouse phantom. Regional [¹⁸F]FDDNP retention in mouse brain was quantified in terms of the relative distribution volume (DVR) using Logan’s graphical analysis with cerebellum as a reference region. Results  Except for a lower maximum brain uptake of radioactivity in transgenic animals, the regional brain kinetics as well as DVR values of [¹⁸F]FDDNP appeared to be similar in both groups of animals. Also for FDG, regional radioactivity retention was almost identical in the brains of transgenic and control animals. Conclusions  We could not detect regionally increased [¹⁸F]FDDNP binding and regionally decreased FDG binding in the brains of Tg2576 transgenic versus wild-type mice. However, small group differences in signal might have been masked by inter-animal variability. In addition, technical limitations of the applied method (partial volume effect, spatial resolution) for measurements in such small organs as mouse brain have to be taken into consideration.     

Evaluation of 99mTc-citrate, 67Gacitrate and 99mTc(V) dimercaptosuccinic acid for the scintigraphic visualization of acute appendicitis

An experimental study was planned to evaluate ^99mTc-citrate, ⁶⁷Gacitrate and ^99mTc(V) dimercaptosuccinic acid (DMSA) as agents for the visualization of acute appendicitis. Appendiceal ligation was performed through a midline incision in 24 rabbits. Twenty-four hours later the animals were divided into three equal groups. The rabbits were injected through the aurical vein with 1 mCi (37 MBq) ^99mTc-citrate in group I, 0.5 mCi (18.5 MBq) ⁶⁷Ga-citrate in group II and 1 mCi (37 MBq) ^99mTc(V) DMSA in group III. After 3 h, static images of the rabbits were obtained with a gamma camera. There were positive images in seven, six and five rabbits in groups I, II and III respectively. The image quality was better in group I than in the other groups. Also, the mean uptake in group I was significantly higher than those of other two groups (P < 0.05). There was no significant difference between groups II and III (P > 0.05). All rabbits had appendicitis confirmed histologically. In conclusion, these results show that 99mTc-citrate is preferable to 67Ga-citrate and ^99mTc(V) DMSA for the differential diagnosis of acute abdominal inflammations such as appendicitis, because of higher concentration ratios, simple and rapid preparation, low cost, excretion mainly through the kidneys and fast blood clearance.     

Evaluation of [123I]IBZM pinhole SPECT for the detection of striatal dopamine D2 receptor availability in rats

Single photon emission computed tomography (SPECT) and MRI coregistration have been assessed to characterize striatal dopamine D2/D3 receptor (D2/D3R) availability in rats following injection of the D2 and D3R radioligand [123I] iodobenzamide ([123I]IBZM). High-resolution SPECT data were obtained with a pinhole collimator. In order to precisely estimate brain regions of low radioligand uptake, SPECT images were coregistered onto a MRI template with high accuracy (maximum mismatch 1.1 mm). To evaluate an adequate dose of radioligand to be administered without exceeding the radioligand-to-receptor occupancy >5% and to define an appropriate time period for image acquisition, three untreated groups of animals received 29.6, 37, and 44.4 MBq of [123I]IBZM and underwent five consecutive SPECT acquisitions lasting 64 min each. Ratio calculations between specific striatal radioligand uptake and nondisplaceable cerebellar uptake revealed a secular equilibrium between 75 and 355 min post-tracer application in all three animal groups. Consequently, since the highest regional uptake values were obtained in the animal group receiving 44.4 MBq [123I]IBZM, this injection dose was considered to be appropriate. Finally, the capacity of the imaging method to detect distinct severity levels of striatal dopamine D2/D3 receptor loss was tested in a low, medium, and high dose quinolinic acid (QA) animal model of Huntington's disease. Motor impairment indicative of striatal dysfunction was monitored using amphetamine-induced rotational behavior and locomotor activity. Loss of striatal D2/D3R bearing medium-sized spiny neurons was assessed by DARPP-32 immunohistochemistry and compared to [123I]IBZM binding. Optical density measures of DARPP-32 immunohistochemistry demonstrated QA dose-dependent mild to subtotal unilateral striatal lesions ranging from 29.4% to 96.9% when compared to the nonlesioned side. Linear regression analysis showed that measurements of striatal DARPP-32 optical density and striatal [123I]IBZM uptake of the lesioned side were highly correlated (r2=0.83; P<0.001) whereas correlation with locomotor activity was less tight (r2=0.23; P<0.05; amphetamine-induced rotational behavior was not significantly correlated). This is the first study to demonstrate that in vivo [123I]IBZM SPECT and MRI coregistration are highly sensitive and, in contrast to behavioral measures, accurately detect mild to subtotal striatal lesions by measuring loss of D2/D3R availability. SPECT-MRI-based estimation of regional [123I]IBZM uptake provides a cost effective and widely available in vivo imaging technique for assessing striatal integrity in animal studies.