Development and preclinical characterisation of <Superscript>99m</Superscript>Tc-labelled Affibody molecules with reduced renal uptake

Purpose  Affibody molecules are low molecular weight proteins (7 kDa), which can be selected to bind to tumour-associated target proteins with subnanomolar affinity. Because of rapid tumour localisation and clearance from nonspecific compartments, Affibody molecules are promising tracers for molecular imaging. Earlier, ^99mTc-labelled Affibody molecules demonstrated specific targeting of tumour xenografts. However, the biodistribution was suboptimal either because of hepatobiliary excretion or high renal uptake of the radioactivity. The goal of this study was to optimise the biodistribution of Affibody molecules by chelator engineering. Materials and methods  Anti-HER2 Z_HER2:342 Affibody molecules, carrying the mercaptoacetyl-glutamyl-seryl-glutamyl (maESE), mercaptoacetyl-glutamyl-glutamyl-seryl (maEES) and mercaptoacetyl-seryl-glutamyl-glutamyl (maSEE) chelators, were prepared by peptide synthesis and labelled with ^99mTc. The tumour-targeting capacity of these conjugates was compared with each other and with the best previously available conjugate, ^99mTc-maEEE-Z_HER2:342, in nude mice bearing SKOV-3 xenografts. The tumour-targeting capacity of the most promising conjugate, ^99mTc-maESE-Z_HER2:342, was compared with radioiodinated Z_HER2:342. Results  All novel conjugates demonstrated successful tumour targeting and a low degree of hepatobiliary excretion. The renal uptakes of serine-containing conjugates, 33 ± 5, 68 ± 21 and 71 ± 10%IA/g, for^99mTc-maESE-Z_HER2:342, ^99mTc-maEES-Z_HER2:342 and ^99mTc-maSEE-Z_HER2:342, respectively, were significantly reduced in comparison with ^99mTc-maEEE-Z_HER2:342 (102 ± 13%IA/g). For ^99mTc-maESE-Z_HER2:342, a tumour uptake of 9.6 ± 1.8%IA/g and a tumour-to-blood ratio of 58 ± 6 were reached at 4 h p.i. Conclusions  A combination of serine and glutamic acid residues in the chelator sequence confers increased renal excretion and relatively low renal uptake of ^99mTc-labelled Affibody molecules. In combination with preserved targeting capacity, this improved imaging of targets in abdominal area.     

Functional imaging of multidrug resistance in an orthotopic model of osteosarcoma using 99mTc-sestamibi

Purpose The purpose of this work was the development of an orthotopic model of osteosarcoma based on luciferase-expressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with ^99mTc-sestamibi. Methods Doxorubicin-sensitive (143B-luc⁺) and resistant (MNNG/HOS-luc⁺) osteosarcoma cell lines expressing different levels of P-glycoprotein and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumour growth was monitored weekly by bioluminescence imaging and X-ray. After tumour growth, a ^99mTc-sestamibi dynamic study was performed. A subset of animals was pre-treated with an MDR inhibitor (PSC833). Images were analysed for calculation of ^99mTc-sestamibi washout half-life (t _1/2), percentage washout rate (%WR) and tumour/non-tumour (T/NT) ratio. Results A progressively increasing bioluminescent signal was detected in the proximal tibia after 2 weeks. The t _1/2 of ^99mTc-sestamibi was significantly shorter (p < 0.05) in drug-resistant MNNG/HOS-luc⁺ tumours (t _1/2 = 87.3 ± 15.7 min) than in drug-sensitive 143B-luc⁺ tumours (t _1/2 = 161.0 ± 47.4 min) and decreased significantly with PSC833 (t _1/2 = 173.0 ± 24.5 min, p < 0.05). No significant effects of PSC833 were observed in 143B-luc⁺ tumours. The T/NT ratio was significantly lower (p < 0.05) in MNNG/HOS-luc⁺ tumours than in 143B-luc⁺ tumours at early (1.55 ± 0.22 vs 2.14 ± 0.36) and delayed times (1.12 ± 0.11 vs 1.62 ± 0.33). PSC833 had no significant effects on the T/NT ratios of either tumour. Conclusion The orthotopic injection of tumour cells provides an animal model suitable for functional imaging of MDR. In vivo bioluminescence imaging allows the non-invasive monitoring of tumour growth. The kinetic analysis of ^99mTc-sestamibi washout provides information on the functional activity of MDR related to P-glycoprotein expression and its pharmacological inhibition in osteosarcoma.     

In vivo imaging of radiation-induced tissue apoptosis by <Superscript>99m</Superscript>Tc(I)-his<Subscript>6</Subscript>-annexin A5

Objective  

A recombinant annexin A5 with the N-terminal extension of six histidine residues was labeled with ^99mTc(I)-tricarbonyl ion to produce the ^99mTc-labeled annexin A5, referred to ^99mTc(I)-his₆-annexin A5. We have explored the agent as an effective imaging probe for in vivo detecting the apoptosis of internal tissue subjected with high radiation doses in a γ-irradiated mouse model.     

Comparison of <Superscript>99m</Superscript>Tc-annexin A5 with <Superscript>18</Superscript>F-FDG for the detection of atherosclerosis in ApoE−/− mice

Purpose ^99mTc-annexin A5, a marker of ongoing apoptosis, and ¹⁸F-FDG, a marker of the increased metabolism of inflammatory cells, are supposed to be useful in the detection of metabolically active atheroma. This study reports a comparison of the intralesional distribution of these tracers in relation to lesion development in ApoE−/− mice. Methods Male ApoE−/− mice (n = 12–14/group) were maintained on a Western-type diet after the age of 5 weeks. At 25 weeks, ^99mTc-annexin A5 or ¹⁸F-FDG was injected and the aortas were harvested for autoradiography (ARG) and Oil Red O staining. Regional radioactivity accumulation was compared in relation to the Oil Red O staining score (ranging from 0 to 3, a semiquantitative parameter for evaluating lesion development). Results Both ^99mTc-annexin A5 and ¹⁸F-FDG showed preferential uptake into atherosclerotic lesions, with higher uptake levels for ¹⁸F-FDG (mean, 56.07 %ID×kg/m²) than for ^99mTc-annexin A5 (mean, 10.38 %ID×kg/m²). The regional uptake levels of each tracer correlated with the Oil Red O staining score (r = 0.65, p < 0.05 for ^99mTc-annexin A5; r = 0.56, p < 0.05 for ¹⁸F-FDG). The uptake ratios of advanced lesions (score >0.5) to early lesions (score <0.5) were significantly higher for ^99mTc-annexin A5 than for ¹⁸F-FDG (f = 4.73, p = 0.03). Conclusion Both ^99mTc-annexin A5 and ¹⁸F-FDG accumulate in atherosclerotic lesions and correlate with the severity of each lesion. The higher absolute uptake levels of ¹⁸F-FDG may be advantageous for lesion detection, whereas the preferential uptake of ^99mTc-annexin A5 in advanced lesions may be a useful indicator of late-stage lesions or vulnerable plaque transformation.     

Targeting murine heart and brain: visualisation conditions for multi-pinhole SPECT with <Superscript>99m</Superscript>Tc- and <Superscript>123</Superscript>I-labelled probes

Purpose  The study serves to optimise conditions for multi-pinhole SPECT small animal imaging of ¹²³I- and ^99mTc-labelled radiopharmaceuticals with different distributions in murine heart and brain and to investigate detection and dose range thresholds for verification of differences in tracer uptake. Methods  A Triad 88/Trionix system with three 6-pinhole collimators was used for investigation of dose requirements for imaging of the dopamine D₂ receptor ligand [¹²³I]IBZM and the cerebral perfusion tracer [^99mTc]HMPAO (1.2–0.4 MBq/g body weight) in healthy mice. The fatty acid [¹²³I]IPPA (0.94 ± 0.05 MBq/g body weight) and the perfusion tracer [^99mTc]sestamibi (3.8 ± 0.45 MBq/g body weight) were applied to cardiomyopathic mice overexpressing the prostaglandin EP₃ receptor. Results  In vivo imaging and in vitro data revealed 45 kBq total cerebral uptake and 201 kBq cardiac uptake as thresholds for visualisation of striatal [¹²³I]IBZM and of cardiac [^99mTc]sestamibi using 100 and 150 s acquisition time, respectively. Alterations of maximal cerebral uptake of [¹²³I]IBZM by >20% (116 kBq) were verified with the prerequisite of 50% striatal of total uptake. The labelling with [^99mTc]sestamibi revealed a 30% lower uptake in cardiomyopathic hearts compared to wild types. [¹²³I]IPPA uptake could be visualised at activity doses of 0.8 MBq/g body weight. Conclusion  Multi-pinhole SPECT enables detection of alterations of the cerebral uptake of ¹²³I- and ^99mTc-labelled tracers in an appropriate dose range in murine models targeting physiological processes in brain and heart. The thresholds of detection for differences in the tracer uptake determined under the conditions of our experiments well reflect distinctions in molar activity and uptake characteristics of the tracers. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Noninvasive monitoring the biology of atherosclerotic plaque development with radiolabeled annexin V and matrix metalloproteinase inhibitor in spontaneous atherosclerotic mice

Objectives  

To compare the ability of ^99mTc-labeled broad-based matrix metalloproteinase inhibitor (RP805) (MPI) and ^99mTc-annexin V to identify more advanced atherosclerotic disease in apolipoprotein E-null (apoE^−/−) mice.     

99mTc-sestamibi kinetics predict myocardial viability in a perfused rat heart model

Introduction ^99mTc-sestamibi has been proposed as a viability imaging agent. The purposes of this study were: (1) to determine the relationship between myocardial viability and ^99mTc-sestamibi kinetics using perfused rat heart models across a full spectrum of viability, (2) to do so under conditions where myocardial flow was controlled and held constant, and (3) to do so using multiple quantitative methods to assess myocardial viability. Methods Twenty-three isolated rat hearts were perfused retrogradely with a modified Krebs-Henseleit (KH) solution. Four groups were studied: controls (C, n = 6), stunned (S, n = 6), ischemic-reperfused (IR, n = 6), and calcium injured (CAL, n = 5). Following a 20-min baseline and subsequent treatment phase, ^99mTc-sestamibi was infused over 60 min (uptake) followed by 60 min clearance. Treatment phases consisted of 20 min no flow for S, 60 min no flow followed by 60 min reflow for IR, and 10 min infusion of KH solution without calcium followed by 20 min infusion of KH solution with 2 times normal calcium for CAL hearts. Creatine kinase (CK) assay, triphenyltetrazolium chloride (TTC) staining, and transmission electron microscopic (TEM) analysis were used to determine tissue viability. Results Myocardial peak ^99mTc-sestamibi uptake (%id) was significantly decreased in IR (4.11 ± 0.22 SEM; p < 0.05) and CAL (1.07 ± 0.13; p < 0.05), but not in S (4.88 ± 0.17) as compared with C (5.99 ± 0.50). One hour fractional retention was 79.3 ± 1.9% for C, 80.3 ± 1.3% for S (p = n.s.), 79.1 ± 1.8% for IR (p = n.s.), and 14.9 ± 4.3% for CAL (p < 0.05 compared to all other groups). ^99mTc-sestamibi absolute retention (%id) 1 h after the end of tracer administration was significantly decreased in IR (3.26 ± 0.23) and CAL (0.15 ± 0.02) as compared with both S (3.92 ± 0.16) and C (4.52 ± 0.32) (p < 0.05). CK increased significantly from baseline in the IR and CAL hearts. TTC determined percent viability was 100 ± 0% for C, 98.3 ± 1.1% for S, 82.8 ± 2.6% for IR, and 0.0 ± 0% for CAL. TEM analysis supported these findings. End tracer activity was significantly correlated with TTC determined percentage viable myocardium (r = 0.93, p < 0.05) and CK leak (r = −0.90, p < 0.05). Conclusion ^99mTc-sestamibi myocardial activity is significantly reduced in areas of nonviability after 1 h of tracer uptake and 1 h of tracer clearance. There is a linear correlation between myocardial viability, as determined by three independent methods, and tracer activity. This work was supported by the American Heart Association, the Anne and Henry Zarrow Foundation, and the William K. Warren Medical Research Foundation.     

Estimate of myocardial salvage in late presentation acute myocardial infarction by comparing functional and perfusion abnormalities in predischarge gated SPECT

Purpose We hypothesized that, because of persistent stunning, the extent of post-treatment functional abnormalities detected using gated single-photon emission computed tomography (SPECT) could be representative of the initial risk area in acute myocardial infarction (AMI) treated by reperfusion therapy. Materials and methods In 48 AMI patients, we acquired two ^99mTc-sestamibi gated SPECT studies (at admission with tracer injection before treatment and at discharge 5 to 10 days later). We assessed the myocardial salvage defined by the admission minus predischarge summed rest score, and we compared it with the value obtained by subtracting the extent of perfusion defect from the extent of wall motion or wall thickening abnormalities in predischarge gated SPECT. Myocardial salvage was expressed as salvage index (salvaged myocardium divided by initial risk area). Results There was a good correlation between summed rest score salvage index and wall motion (Spearman’s ρ = 0.754, p < 0.0001) or wall thickening salvage index (Spearman’s ρ = 0.798, p < 0.0001). The wall thickening salvage index was able to classify correctly the patients that had a summed rest score salvage index ≥ 0.10 with 73% sensitivity, 88% specificity, and 83% accuracy. The wall motion salvage index was highly sensitive (91%) but poorly specific (13%, p < 0.002 vs wall thickening salvage index) and less accurate (69%, p < 0.05 vs wall thickening salvage index). Conclusions ^99mTc-sestamibi gated SPECT allows assessing myocardial salvage using only post-treatment data. The salvage index derived using wall thickening as surrogate of admission perfusion defect correlates well with the salvage index measured by comparing pre- and post-treatment perfusion defects.     

Differential diagnosis of solitary pulmonary nodules using <Superscript>99m</Superscript>Tc-3P<Subscript>4</Subscript>-RGD<Subscript>2</Subscript> scintigraphy

Purpose  

Targeting of integrin α_νβ₃ with molecular imaging agents offers great potential in early detection and monitoring of tumour angiogenesis. Recently, an RGD (Arg-Gly-Asp) tracer, ^99mTc-3P₄-RGD₂, with high affinity to integrin α_νβ₃ and in vivo tumour uptake was developed. In this study, we evaluate the feasibility of this novel radiotracer in the noninvasive differentiation of solitary pulmonary nodules (SPNs).     

Radioembolisation with <Superscript>90</Superscript>Y-microspheres: dosimetric and radiobiological investigation for multi-cycle treatment

Introduction  Radioembolisation with ⁹⁰Y-microspheres is a new locoregional treatment of hepatic lesions, usually applied as single cycle. Multi-cycle treatments might be considered as a strategy to improve the risk-benefit balance. With the aim to derive suitable information for patient tailored therapy, available patients’ dosimetric data were reviewed according to the linear–quadratic model and converted into biological effective dose (BED) values. Single vs. multi-cycle approaches were compared through radiobiological perspective. Materials and methods  Twenty patients with metastatic lesions underwent radioembolisation. The ⁹⁰Y-administered activity (AA) was established in order to respect a precautionary limit dose (40 Gy) for the non-tumoral liver (NTL). BED was calculated setting α/β = 2.5 Gy (NTL), 10 Gy (tumours); T _1/2,eff = T _1/2,phys = 64.2 h; T _1/2,rep = 2.5 h (NTL), 1.5 h (tumours). The BED to NTL was considered as a constraint for multi-cycle approach. The AA for two cycles and the percent variations of AA, tumour dose, BED were estimated. Results  In one-cycle, for a prescribed BED to NTL of 64 Gy (NTL dose = 40 Gy), AA was 1.7 (0.9–3.2) GBq, tumour dose was 130 (65–235) Gy, and tumour BED was 170 (75–360) Gy. Considering two cycles, ∼15% increase was found for AA and dose to NTL, with unvaried BED for NTL. Tumour dose increase was 20 (10–35) Gy; tumour BED increase was 10 (3–11) Gy. In different protocols allowing 80 Gy to NTL, the BED sparing estimated was ∼50 Gy (two cycles) and 65 Gy (three cycles). Conclusions  From a radiobiological perspective, multi-cycle treatments would allow administering higher activities with increased tumour irradiation and preserved radiation effects on NTL. Trials comparing single vs. multiple cycles are suggested.     

Evaluation of computer-aided detection and dual energy software in detection of peripheral pulmonary embolism on dual-energy pulmonary CT angiography

Purpose  

To evaluate the sensitivity of computer-aided detection(CAD) and dual-energy software(‘Lung PBV’, ‘Lung Vessels’) for detecting peripheral pulmonary embolism(PE).     

Measurement of central µ-opioid receptor binding in vivo with PET and [<Superscript>11</Superscript>C]carfentanil: a test–retest study in healthy subjects

Purpose  [¹¹C]Carfentanil has been widely used in positron emission tomography (PET) studies for measuring μ-opioid receptor binding in humans, but the reproducibility of the binding parameter estimates is unknown. Materials and methods  Eight healthy volunteers were scanned twice during the same day with [¹¹C]carfentanil PET, and binding to receptors was assessed with both reference tissue and arterial plasma input-based models using region of interest (ROI) and voxel-based quantification. Results  The two-tissue compartmental model distribution volume (V_T) was highly reproducible as indicated by low variability (VAR < 6%) and high intraclass correlation coefficients (ICC > 0.93). BP_ND (BP relative to the nondisplaceable tissue compartment) was also highly reproducible (VAR < 10%, ICC > 0.90) both at ROI- and voxel-level, and reference tissue-based models provided stable estimates after 40 min. Conclusions  The reproducibility of [¹¹C]carfentanil binding parameter estimates is excellent with outcome measures based on both arterial plasma and reference tissue input, and a scanning time of 40 min appears sufficient.     

Prediction of functional recovery after revascularization using quantitative gated myocardial perfusion SPECT: a multi-center cohort study in Japan

Backgrounds  Prediction of left ventricular functional recovery is important after myocardial infarction. The impact of quantitative perfusion and motion analyses with gated single-photon emission computed tomography (SPECT) on predictive ability has not been clearly defined in multi-center studies. Methods  A total of 252 patients with recent myocardial infarction (n = 74) and old myocardial infarction (n = 175) were registered from 25 institutions. All patients underwent resting gated SPECT using ^99mTc-hexakis-2-methoxy-isobutyl isonitrile (MIBI) and repeated the study after revascularization after an average follow-up period of 132 ± 81 days. Visual and quantitative assessment of perfusion and wall motion were performed in 5,040 segments. Results  Non-gated segmental percent uptake and end-systolic (ES) percent uptake were good predictors of wall motion recovery and significantly differed between improved and non-improved groups (66 ± 17% and 55 ± 18%, p < 0.0001 for non-gated; 64 ± 16% and 51 ± 17% for ES percent uptake, p < 0.0001). The area under the curve of receiver operating characteristics curve for non-gated percent uptake, ES percent uptake, end-diastolic percent uptake and visual perfusion defect score was 0.70, 0.71, 0.61, and 0.56, respectively. Sensitivity and specificity of percent uptake were 68% and 64% for non-gated map and 80% and 52% for ES percent uptake map. An optimal threshold for predicting segmental improvement was 63% for non-gated and 52% for ES percent uptake values. Conclusion  Segmental ^99mTc-MIBI uptake provided a useful predictor of wall motion improvement. Application of quantitative approach with non-gated and ES percent uptake enhanced predictive accuracy over visual analysis particularly in a multi-center study.     

<Superscript>99m</Superscript>TcO(MAG<Subscript>2</Subscript>-3G<Subscript>3</Subscript>-dimer): a new integrin α<Subscript>v</Subscript>β<Subscript>3</Subscript>-targeted SPECT radiotracer with high tumor uptake and favorable pharmacokinetics

Purpose  

This report presents the synthesis of a cyclic RGD dimer conjugate, MAG₂-G₃-E[G₃-c(RGDfK)]₂ (MAG₂-3G₃-dimer, G₃ = Gly-Gly-Gly, MAG₂ = S-benzoyl mercaptoacetylglycylglycyl), and evaluation of its ^99mTc complex, ^99mTcO(MAG₂-3G₃-dimer), as a new radiotracer for imaging the tumor integrin α_vβ₃ expression.     

Biokinetics and dosimetry analysis in healthy volunteers for a two-injection (rest-stress) protocol of the myocardial perfusion imaging agent technetium 99m-labeled Q3

Background  

Trans (N,N′-ethylene bis(acetylacetoneimine)) bis(tris(3-methoxy-1-propyl) phosphine) ^99mTc(III) (^99mTc-Q3) has been developed for myocardial perfusion imaging. Biokinetic studies and dosimetry analysis have been completed for six healthy volunteers.     

Technetium-99m pyrophosphate/thallium-201 dual-isotope SPECT imaging predicts reperfusion injury in patients with acute myocardial infarction after reperfusion

Purpose  Microcirculatory failure after reperfusion is clinically indicated to cause reperfusion injury whereas excessive intracellular calcium ion overload is experimentally proved as a key mechanism of reperfusion injury. We hypothesized that technetium-99m (^99mTc) pyrophosphate (Tc-PYP) uptake in injured but viable infarct-related myocardium with preserved myocardial perfusion after reperfusion estimated by thallium-201 (²⁰¹Tl) uptake would be associated with final functional recovery. Methods  Dual-isotope Tc-PYP/²⁰¹Tl single-photon emission computed tomography (SPECT) was performed 2 days after successful reperfusion therapy in patients with first acute myocardial infarction, and 50 patients (63 ± 13 years old, female 22%) with preserved ²⁰¹Tl uptakes of ≥50% in reperfused myocardium was followed for 1 month. Tc-PYP uptake was assessed as the heart-to-sternum (H/S) ratio. Two-dimensional echocardiography was also performed 2 days and 1 month after reperfusion to evaluate functional recovery. Results  High Tc-PYP uptake, defined as the H/S ratio ≥0.81, was predictive of chronic phase no functional recovery (73.7% in 14 of 19 patients with high uptake vs 16.1% in five of 31 patients without those, p < 0.0001). After adjustment for potential confounding variables, including electrocardiographic persistent ST segment elevation at 1 h after reperfusion, high Tc-PYP uptake remained independently predictive of no functional recovery with odds ratio of 8.7 (95% confidential interval = 2 to 38.7; p = 0.005). Conclusion  High Tc-PYP uptake in reperfused but viable infarct-related myocardium was a powerful predictor of no functional recovery, which may reflect excessive intracellular calcium ion overload caused by reperfusion injury. Tc-PYP/²⁰¹Tl dual-isotope SPECT imaging can provide prognostic information after reperfusion.     

Absolute quantitation of myocardial blood flow with <Superscript>201</Superscript>Tl and dynamic SPECT in canine: optimisation and validation of kinetic modelling

Purpose ²⁰¹Tl has been extensively used for myocardial perfusion and viability assessment. Unlike ^99mTc-labelled agents, such as ^99mTc-sestamibi and ^99mTc-tetrofosmine, the regional concentration of ²⁰¹Tl varies with time. This study is intended to validate a kinetic modelling approach for in vivo quantitative estimation of regional myocardial blood flow (MBF) and volume of distribution of ²⁰¹Tl using dynamic SPECT. Methods Dynamic SPECT was carried out on 20 normal canines after the intravenous administration of ²⁰¹Tl using a commercial SPECT system. Seven animals were studied at rest, nine during adenosine infusion, and four after beta-blocker administration. Quantitative images were reconstructed with a previously validated technique, employing OS-EM with attenuation-correction, and transmission-dependent convolution subtraction scatter correction. Measured regional time–activity curves in myocardial segments were fitted to two- and three-compartment models. Regional MBF was defined as the influx rate constant (K ₁) with corrections for the partial volume effect, haematocrit and limited first-pass extraction fraction, and was compared with that determined from radio-labelled microspheres experiments. Results Regional time–activity curves responded well to pharmacological stress. Quantitative MBF values were higher with adenosine and decreased after beta-blocker compared to a resting condition. MBFs obtained with SPECT (MBF_SPECT) correlated well with the MBF values obtained by the radio-labelled microspheres (MBF_MS) (MBF_SPECT = −0.067 + 1.042 × MBF_MS, p < 0.001). The three-compartment model provided better fit than the two-compartment model, but the difference in MBF values between the two methods was small and could be accounted for with a simple linear regression. Conclusion Absolute quantitation of regional MBF, for a wide physiological flow range, appears to be feasible using ²⁰¹Tl and dynamic SPECT.     

Early detection and monitoring of cartilage alteration in the experimental meniscectomised guinea pig model of osteoarthritis by <Superscript>99m</Superscript>Tc-NTP 15-5 scintigraphy

Purpose This study in the meniscectomised guinea pig aimed to demonstrate that the radiotracer ^99mTc-NTP 15-5 would have pathophysiological validity for in vivo osteoarthritis imaging. Methods The specificity of ^99mTc-NTP 15-5 for cartilage was determined in healthy animals (n = 13), by tissue radioactivity counting, joint autoradiography and scintigraphy. ^99mTc-NTP 15-5 scintigraphy was performed at 20, 50, 80, 115, 130, 150 and 180 days after medial meniscectomy (n = 10 MNX) or sham operation (n = 5), and scintigraphic ratios (operated/contralateral) were calculated for femoral (F) and tibial (T) areas. F and T ratios were compared with those of ^99mTc-MDP bone scintigraphy. At the study end-point, autoradiographic analysis of joint ^99mTc-NTP 15-5 distribution and macroscopic scoring of cartilage integrity were performed. Results The high and specific accumulation of ^99mTc-NTP 15-5 in normal cartilage (about 5.5 ± 1.7 % of injected dose/g of tissue), which permitted joint imaging with high contrast, was affected by osteoarthritis. In the MNX group, ^99mTc-NTP 15-5 accumulation in cartilage within the operated joint, relative to the contralateral joint, was observed to change in the same animals as pathology progressed. Although F and T ratios were significantly higher in MNX (F = 1.7 ± 0.2; T = 1.6 ± 0.1) than in shams (F = 1.0 ± 0.1; T = 1.0 ± 0.1) at day 50, they were significantly lower in MNX (F = 0.6 ± 0.1; T = 0.7 ± 0.1) than in shams (F = 1.0 ± 0.1; T = 0.9 ± 0.1) at day 180. No change in ^99mTc-MDP uptake was observed over 6 months. Macroscopic analysis confirmed features of osteoarthritis only in MNX knees. Conclusion These results in MNX guinea pigs provide additional support for the use of ^99mTc-NTP 15-5 for in vivo imaging of osteoarthritis.     

<Superscript>99m</Superscript>Tc-Annexin A5 for noninvasive characterization of atherosclerotic lesions: imaging and histological studies in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits

Purpose Apoptosis is commonly observed in advanced atherosclerotic lesions. ^99mTc-annexin A5 (^99mTc-annexin V) has been proposed as a potential tracer for imaging apoptosis in atherosclerotic plaques. Accordingly, we determined the usefulness of ^99mTc-annexin A5 as an atherosclerosis imaging tracer in a rabbit model (myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits; WHHLMI rabbits) of spontaneous atherosclerosis. Methods The WHHLMI and control rabbits were injected intravenously with ^99mTc-annexin A5. After in vivo planar imaging, the radioactivity in the aorta was measured. Autoradiography, TUNEL staining, Azan-Mallory staining and immunohistological studies were performed serially throughout the aorta. Results ^99mTc-Annexin A5 accumulation in the aorta of the WHHLMI rabbits was 5.6-fold higher than in that of control rabbits. Autoradiography showed heterogeneous multifocal accumulation of ^99mTc-annexin A5 in WHHLMI rabbits. ^99mTc-Annexin A5 accumulation was highest in the atheromatous lesions (6.2 ± 2.5, %ID × BW/mm² × 10³), followed in decreasing order by neointimal (4.9 ± 1.3), fibroatheromatous (4.5 ± 1.9), and collagen-rich lesions (3.3 ± 1.4). The regional ^99mTc-annexin A5 accumulation was significantly correlated with the TUNEL-positive cell density, macrophage density and “vulnerability index,” an index of the morphological destabilized characteristics. The in vivo imaging clearly visualized the atherosclerotic lesions in WHHLMI rabbits. Conclusion The present study in WHHLMI rabbits showed higher ^99mTc-annexin A5 accumulation in grade IV atheroma than in other more stable lesions. ^99mTc-Annexin A5 may be useful in identifying atheroma that is at higher risk for rupture and possibly in assessing the response to anti-atherosclerotic therapy.     

Evaluation of dynamic row-action maximum likelihood algorithm reconstruction for quantitative 15O brain PET

Objective  

A modified version of row-action maximum likelihood algorithm (RAMLA) using a ‘subset-dependent’ relaxation parameter for noise suppression, or dynamic RAMLA (DRAMA), has been proposed. The aim of this study was to assess the capability of DRAMA reconstruction for quantitative ¹⁵O brain positron emission tomography (PET).