| 1. |
- Wållberg, Helena, et al.
(author)
-
HER2-Positive Tumors Imaged Within 1 Hour Using a Site-Specifically C-11-Labeled Sel-Tagged Affibody Molecule
- 2012
-
In: Journal of Nuclear Medicine. - Stockholm : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 53:9, s. 1446-1453
-
Journal article (peer-reviewed)abstract
- A rapid, reliable method for distinguishing tumors or metastases that overexpress human epidermal growth factor receptor 2 (HER2) from those that do not is highly desired for individualizing therapy and predicting prognoses. In vivo imaging methods are available but not yet in clinical practice; new methodologies improving speed, sensitivity, and specificity are required. Methods: A HER2-binding Affibody molecule, Z(HER2:342), was recombinantly fused with a C-terminal selenocysteine-containing tetrapeptide Sel-tag, allowing site-specific labeling with either C-11 or Ga-68, followed by biodistribution studies with small-animal PET. Dosimetry data for the 2 radiotracers were compared. Imaging of HER2-expressing human tumor xenografts was performed using the C-11-labeled Affibody molecule. Results: Both the C-11- and Ga-68-labeled tracers initially cleared rapidly from the blood, followed by a slower decrease to 4-5 percentage injected dose per gram of tissue at 1 h. Final retention in the kidneys was much lower (>5-fold) for the C-11-labeled protein, and its overall absorbed dose was considerably lower. C-11-Z(HER2:342) showed excellent tumor-targeting capability, with almost 10 percentage injected dose per gram of tissue in HER2-expressing tumors within 1 h. Specificity was demonstrated by preblocking binding sites with excess ligand, yielding significantly reduced radiotracer uptake (P = 0.002), comparable to uptake in tumors with low HER2 expression. Conclusion: To our knowledge, the Sel-tagging technique is the first that enables site-specific C-11-radiolabeling of proteins. Here we present the finding that, in a favorable combination between radionuclide half-life and in vivo pharmacokinetics of the Affibody molecules, C-11-labeled Set-tagged Z(HER2:342) can successfully be used for rapid and repeated PET studies of HER2 expression in tumors.
|
|
| 2. |
- Ahlgren, Sara, et al.
(author)
-
Targeting of HER2-Expressing Tumors Using 111In-ABY-025, a Second-Generation Affibody Molecule with a Fundamentally Reengineered Scaffold
- 2010
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 51:7, s. 1131-1138
-
Journal article (peer-reviewed)abstract
- Overexpression of HER2 in breast carcinomas predicts response to trastuzumab therapy. Affibody molecules based on a non-immunoglobulin scaffold have demon-strated high potential for in vivo molecular imaging of HER2-expressing tumors. Re-engineering of the molecular scaffold has led to a second generation of optimized Affibody molecules, having a surface distinctly different from the parental protein domain from staphylococcal protein A. The new tracer showed further increased melting point, stability and overall hydrophilicity compared to the parental molecule, and was shown to be more amenable for chemical peptide synthesis. The goal of this study was to assess potential effects of this extensive re-engineering on HER2 targeting, using ABY-025, a DOTA conjugated variant of the novel tracer. Methods: 111In-ABY-025 was compared with previously evaluated parent HER2-binding Affibody tracers in vitro and in vivo. The in vivo behavior was further evaluated in mice bearing SKOV-3 xenografts, in rats and in cynomolgus macaques. Results: 111In-ABY-025 bound specifically to HER2 in vitro and in vivo. Direct comparison with the previous generation of HER2-binding tracers showed that ABY-025 retained excellent targeting properties. Rapid blood clearance was shown in mice, rats and macaques. A highly specific tumor uptake of 16.7 ± 2.5 %IA/g was seen at 4 h after injection. The tumor-to-blood ratio was 6.3 at 0.5 h, 88 at 4 h, and increased up to 3 days after injection. Gamma camera imaging of tumors was already possible 0.5 h after injection. Furthermore, repeated i.v. administration of ABY-025 did not induce antibody formation in rats. Conclusions: The biodistribution of 111In-ABY-025 was in remarkably good agreement with the parent tracers, despite profound re-engineering of the non-binding surface. The molecule displayed rapid blood clearance in all species investigated and excellent targeting capacity in tumor bearing mice, leading to high tumor-to-organ-ratios and high contrast imaging shortly after injection.
|
|
| 3. |
- Ahlgren, Sara, et al.
(author)
-
Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine
- 2009
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 50:5, s. 781-789
-
Journal article (peer-reviewed)abstract
- The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Small (7 kDa) high-affinity anti-HER2 Affibody molecules may be suitable tracers for SPECT visualization of HER2-expressing tumors. The use of generator-produced (99m)Tc as a label would facilitate the prompt translation of anti-HER2 Affibody molecules into use in clinics. METHODS: A C-terminal cysteine was introduced into the Affibody molecule Z(HER2:342) to enable site-specific labeling with (99m)Tc. Two recombinant variants, His(6)-Z(HER2:342)-Cys (dissociation constant [K(D)], 29 pM) and Z(HER2:2395)-Cys, lacking a His tag (K(D), 27 pM), were labeled with (99m)Tc in yields exceeding 90%. The binding specificity and the cellular processing of Affibody molecules were studied in vitro. Biodistribution and gamma-camera imaging studies were performed in mice bearing HER2-expressing xenografts. RESULTS: (99m)Tc-His(6)-Z(HER2:342)-Cys was capable of targeting HER2-expressing SKOV-3 xenografts in SCID mice, but the liver radioactivity uptake was high. A series of comparative biodistribution experiments indicated that the presence of the His tag caused elevated accumulation in the liver. (99m)Tc-Z(HER2:2395)-Cys, not containing a His tag, showed low uptake in the liver and high and specific uptake in HER2-expressing xenografts. Four hours after injection, the radioactivity uptake values (percentage of injected activity per gram of tissue [%IA/g]) were 6.9 +/- 2.5 (mean +/- SD) %IA/g in LS174T xenografts (moderate level of HER2 expression) and 15 +/- 3 %IA/g in SKOV-3 xenografts (high level of HER2 expression). The corresponding tumor-to-blood ratios were 88 +/- 24 and 121 +/- 24, respectively. Both LS174T and SKOV-3 xenografts were clearly visualized with a clinical gamma-camera 1 h after injection of (99m)Tc-Z(HER2:2395)-Cys. CONCLUSION: The Affibody molecule (99m)Tc-Z(HER2:2395)-Cys is a promising tracer for SPECT visualization of HER2-expressing tumors.
|
|
| 4. |
- Altai, Mohamed, et al.
(author)
-
188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors : preclinical assessment
- 2014
-
In: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 55:11, s. 8-1842
-
Journal article (peer-reviewed)abstract
- UNLABELLED: Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of (99m)Tc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide-based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate (188)Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)-expressing tumors.METHODS: ZHER2:V2 was labeled with (188)Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.RESULTS: Binding of (188)Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that (188)Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.CONCLUSION: (188)Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.
|
|
| 5. |
- Altai, Mohamed, et al.
(author)
-
Feasibility of Affibody-Based Bioorthogonal Chemistry Mediated Radionuclide Pretargeting
- 2016
-
In: Journal of Nuclear Medicine. - : SOC NUCLEAR MEDICINE. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 57:3, s. 431-436
-
Journal article (peer-reviewed)abstract
- Affibody molecules constitute a new class of probes for radionuclide tumor targeting. The small size of Affibody molecules is favorable for rapid localization in tumors and clearance from circulation. However, high renal reabsorption of Affibody molecules prevents the use of residualizing radiometals, including several promising low-energy (beta- and alpha-emitters, for radionuclide therapy. We tested a hypothesis that Affibody-based pretargeting mediated by a bioorthogonal interaction between trans-cyclooctene (TCO) and tetrazine would provide higher accumulation of radiometals in tumor xenografts than in the kidneys. Methods: TCO was conjugated to the anti-human epidermal growth factor receptor 2 (HER2) Affibody molecule Z(2395). DOTA-tetrazine was labeled with In-111 and Lu-177. In vitro pretargeting was studied in HER2-expressing SKOV-3 and BT474 cell lines. In vivo studies were performed on BALB/C nu/nu mice bearing SKOV-3 xenografts. Results: I-125-Z(2395)-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45 +/- 16 pM. In-111-tetrazine bound specifically and selectively to Z(2325)-TCO pretreated cells. In vivo studies demonstrated HER2-specific I-125-Z(2395)-TCO accumulation in xenografts. TCO-mediated In-111-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z(2395)-TCO. At 1 h after injection, the tumor uptake of In-111-tetrazine and Lu-177-tetrazine was approximately 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of In-111 in comparison with direct targeting. Conclusion: The feasibility of Affibody-based bioorthogonal chemistry-mediated pretargeting was demonstrated. The use of pre-targeting provides a substantial reduction of radiometal accumulation in kidneys, creating preconditions for palliative radionuclide therapy.
|
|
| 6. |
- Altai, Mohamed, et al.
(author)
-
Pretargeted Imaging and Therapy
- 2017
-
In: Journal of Nuclear Medicine. - : SOC NUCLEAR MEDICINE INC. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 58:10, s. 1553-1559
-
Journal article (peer-reviewed)abstract
- In vivo pretargeting stands as a promising approach to harnessing the exquisite tumor-targeting properties of antibodies for nuclear imaging and therapy while simultaneously skirting their pharmacokinetic limitations. The core premise of pretargeting lies in administering the targeting vector and radioisotope separately and having the 2 components combine within the body. In this manner, pretargeting strategies decrease the circulation time of the radioactivity, reduce the uptake of the radionuclide in healthy nontarget tissues, and facilitate the use of short-lived radionuclides that would otherwise be incompatible with antibody-based vectors. In this short review, we seek to provide a brief yet informative survey of the 4 preeminent mechanistic approaches to pretargeting, strategies predicated on streptavidin and biotin, bispecific antibodies, complementary oligonucleotides, and bioorthogonal click chemistry.
|
|
| 7. |
- Anand, Aseem, et al.
(author)
-
Assessing Radiographic Response to 223Ra with an Automated Bone Scan Index in Metastatic Castration-Resistant Prostate Cancer Patients
- 2020
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X .- 1535-5667. ; 61:5, s. 671-675
-
Journal article (peer-reviewed)abstract
- For effective clinical management of patients being treated with 223Ra, there is a need for radiographic response biomarkers to minimize disease progression and to stratify patients for subsequent treatment options. The objective of this study was to evaluate an automated bone scan index (aBSI) as a quantitative assessment of bone scans for radiographic response in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: In a multicenter retrospective study, bone scans from patients with mCRPC treated with monthly injections of 223Ra were collected from 7 hospitals in Sweden. Patients with available bone scans before treatment with 223Ra and at treatment discontinuation were eligible for the study. The aBSI was generated at baseline and at treatment discontinuation. The Spearman rank correlation was used to correlate aBSI with the baseline covariates: alkaline phosphatase (ALP) and prostate-specific antigen (PSA). The Cox proportional-hazards model and Kaplan-Meier curve were used to evaluate the association of covariates at baseline and their change at treatment discontinuation with overall survival (OS). The concordance index (C-index) was used to evaluate the discriminating strength of covariates in predicting OS. Results: Bone scan images at baseline were available from 156 patients, and 67 patients had both a baseline and a treatment discontinuation bone scan (median, 5 doses; interquartile range, 3-6 doses). Baseline aBSI (median, 4.5; interquartile range, 2.4-6.5) was moderately correlated with ALP (r = 0.60, P < 0.0001) and with PSA (r = 0.38, P = 0.003). Among baseline covariates, aBSI (P = 0.01) and ALP (P = 0.001) were significantly associated with OS, whereas PSA values were not (P = 0.059). After treatment discontinuation, 36% (24/67), 80% (54/67), and 13% (9/67) of patients demonstrated a decline in aBSI, ALP, and PSA, respectively. As a continuous variable, the relative change in aBSI after treatment, compared with baseline, was significantly associated with OS (P < 0.0001), with a C-index of 0.67. Median OS in patients with both aBSI and ALP decline (median, 134 wk) was significantly longer than in patients with ALP decline only (median, 77 wk; P = 0.029). Conclusion: Both aBSI at baseline and its change at treatment discontinuation were significant parameters associated with OS. The study warrants prospective validation of aBSI as a quantitative imaging response biomarker to predict OS in patients with mCRPC treated with 223Ra.
|
|
| 8. |
- Antoni, Gunnar, et al.
(author)
-
In Vivo Visualization of Amyloid Deposits in the Heart with C-11-PIB and PET
- 2013
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 54:2, s. 213-220
-
Journal article (peer-reviewed)abstract
- Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-C-11]2-(4'-methylamino-phenyl)-6-hydroxybenzothiazole (C-11-PIB) PET is used in the evaluation of brain amyloidosis. We evaluated the potential use of C-11-PIB PET in systemic amyloidosis affecting the heart. Methods: Patients (n = 10) diagnosed with systemic amyloidosis-including heart involvement of either monoclonal immunoglobulin light-chain (AL) or transthyretin (ATTR) type- and healthy volunteers (n = 5) were investigated with PET/CT using C-11-PIB to study cardiac amyloid deposits and with C-11-acetate to measure myocardial blood flow to study the impact of global and regional perfusion on PIB retention. Results: Myocardial C-11-PIB uptake was visually evident in all patients 15-25 min after injection and was not seen in any volunteer. A significant difference in C-11-PIB retention in the heart between patients and healthy controls was found. The data indicate that myocardial amyloid deposits in patients diagnosed with systemic amyloidosis could be visualized with C-11-PIB. No correlation between C-11-PIB retention index and myocardial blood flow as measured with C-11-acetate was found on the global level, whereas a positive correlation on the segmental level was seen in a single patient. Conclusion: C-11-PIB and PET could be a method to study systemic amyloidosis of type AL and ATTR affecting the heart and should be investigated further both as a diagnostic tool and as a noninvasive method for treatment follow-up.
|
|
| 9. |
- Antoni, Gunnar, et al.
(author)
-
In Vivo Visualization and Quantification of Neutrophil Elastase in Lungs of COVID-19 Patients : A First-in-Humans PET Study with 11C-NES
- 2023
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 64:1, s. 145-148
-
Journal article (peer-reviewed)abstract
- COVID-19 can cause life-threatening lung-inflammation that is suggested to be mediated by neutrophils, whose effector mechanisms in COVID-19 is inexplicit. The aim of the present work is to evaluate a novel PET tracer for neutrophil elastase in COVID-19 patients and healthy controls.METHODS: In this open-label, First-In-Man study, four patients with hypoxia due to COVID-19 and two healthy controls were investigated with positron emission tomography (PET) using the new selective and specific neutrophil elastase PET-tracer [11C]GW457427 and [15O]water for the visualization and quantification of NE and perfusion in the lungs, respectively.RESULTS: [11C]GW457427 accumulated selectively in lung areas with ground-glass opacities on computed tomography characteristic of COVID-19 suggesting high levels on NE in these areas. In the same areas perfusion was severely reduced in comparison to healthy lung tissue as measured with [15O]water.CONCLUSION: The data suggests that NE may be responsible for the severe lung inflammation in COVID-19 patients and that inhibition of NE could potentially reduce the acute inflammatory process and improve the condition.
|
|
| 10. |
- Appel, Lieuwe, et al.
(author)
-
Use of C-11-PE2I PET in Differential Diagnosis of Parkinsonian Disorders
- 2015
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 56:2, s. 234-242
-
Journal article (peer-reviewed)abstract
- In idiopathic Parkinson disease and atypical parkinsonian disorders, central dopaminergic and overall brain functional activity are altered to different degrees, causing difficulties in achieving an unambiguous clinical diagnosis. A dual examination using I-123-FP-CIT (I-123-N-omega-fluoropropyl- 2 beta-carbomethoxy-3 beta-(4-iodophenyl) nortropane, or I-123-ioflupane) SPECT and F-18-FDG PET provides complementary information on dopamine transporter (DAT) availability and overall brain functional activity, respectively. Parametric images based on a single, dynamic C-11-PE2I (N-(3-iodoprop-2E-enyl)-2 beta-carbomethoxy-3 beta-(4-methyl-phenyl) nortropane) scan potentially supply both DAT availability (nondisplaceable binding potential [BPND]) and relative cerebral blood flow (relative delivery [R-1]) at voxel level. This study aimed to evaluate the validity of C-11-PE2I PET against the dual-modality approach using I-123-FP-CIT SPECT and F-18-FDG PET.Methods: Sixteen patients with parkinsonian disorders had a dual examination with F-18-FDG PET and I-123-FP-CIT SPECT following clinical routines and additionally an experimental C-11-PE2I PET scan. Parametric BPND and R-1 images were generated using receptor parametric mapping with the cerebellum as a reference. T1-weighted MR imaging was used for automated definition of volumes of interest (VOI). The DAT VOIs included the basal ganglia, whereas the overall brain functional activity was examined using VOIs across the brain. BPND and R-1 values were compared with normalized I-123-FP-CIT and F-18-FDG uptake values, respectively, using Pearson correlations and regression analyses. In addition, 2 masked interpreters evaluated the images visually, in both the routine and the experimental datasets, for comparison of patient diagnoses.Results: Parametric C-11-PE2I BPND and R-1 images showed high consistency with I-123-FP-CIT SPECT and F-18-FDG PET images. Correlations between C-11-PE2I BPND and I-123-FP-CIT uptake ratios were 0.97 and 0.76 in the putamen and caudate nucleus, respectively. Regional C-11-PE2I R-1 values were moderately to highly correlated with normalized F-18-FDG values (range, 0.61-0.94). Visual assessment of DAT availability showed a high consistency between C-11-PE2I BPND and I-123-FP-CIT images, whereas the consistency was somewhat lower for appraisal of overall brain functional activity using I-123-FP-CIT and F-18-FDG images. Substantial differences were found between clinical diagnosis and both neuro-imaging diagnoses.Conclusion: A single, dynamic C-11-PE2I PET investigation is a powerful alternative to a dual examination with I-123-FP-CIT SPECT and F-18-FDG PET for differential diagnosis of parkinsonian disorders. A large-scale patient study is, however, needed to further investigate distinct pathologic patterns in overall brain functional activity for various parkinsonian disorders.
|
|
| 11. |
- Baum, Richard P, et al.
(author)
-
Molecular imaging of HER2-expressing malignant tumors in breast cancer patients using synthetic 111In- or 68Ga-labeled affibody molecules
- 2010
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 51:6, s. 892-897
-
Journal article (peer-reviewed)abstract
- The clinical utility of a human epidermal growth factor receptor 2 (HER2)-targeting Affibody molecule for detection and characterization of HER2-positive lesions was investigated in patients with recurrent metastatic breast cancer. METHODS: Three patients received (111)In- or (68)Ga-labeled DOTA(0)-Z(HER2:342-pep2) (ABY-002). gamma-Camera, SPECT, or PET/CT images were compared with earlier (18)F-FDG PET/CT results. RESULTS: Administration of radiolabeled ABY-002 was well tolerated. Blood kinetics of radiolabeled ABY-002 showed a first half-life of 4-14 min, second half-life of 1-4 h, and third half-life of 12-18 h. Radiolabeled ABY-002 detected 9 of 11 (18)F-FDG-positive metastases as early as 2-3 h after injection. CONCLUSION: Molecular imaging using (111)In- or (68)Ga-labeled ABY-002 has the potential to localize metastatic lesions in vivo, adds qualitative information not available today by conventional imaging techniques, and may allow the HER2 status to be determined for metastases not amenable to biopsy. To our knowledge, this is the first report on clinical imaging data obtained with a non-immunoglobulin-based scaffold protein.
|
|
| 12. |
- Bergström, Mats, et al.
(author)
-
Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922
- 2008
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 49:7, s. 1204-1210
-
Journal article (peer-reviewed)abstract
- For a PET agent to be successful as a biomarker in early clinical trials of new anticancer agents, some conditions need to be fulfilled: the selected tracer should show a response that is related to the antitumoral effects, the quantitative value of this response should be interpretable to the antitumoral action, and the timing of the PET scan should be optimized to action of the drug. These conditions are not necessarily known at the start of a drug-development program and need to be explored. We proposed a translational imaging activity in which experiments in spheroids and later in xenografts are coupled to modeling of growth inhibition and to the related changes in the kinetics of PET tracers and other biomarkers. In addition, we demonstrated how this information can be used for planning clinical trials. Methods: The first part of this concept is illustrated in a spheroid model with BT474 breast cancer cells treated with the heat shock protein 90 (Hsp90) inhibitor NVP-AUY922. The growth-inhibitory effect after a pulse treatment with the drug was measured with digital image analysis to determine effects on volume with high accuracy. The growth-inhibitory effect was described mathematically by a combined E-max and time course model fitted to the data. The model was then used to simulate a once-per-week treatment, in these experiments the uptake of the PET tracers F-18-FDG and 3'-deoxy-3'-F-18-fluorothymidine (F-18-FLT) was determined at different doses and different time points. Results: A drug exposure of 2 h followed by washout of the drug from the culture medium generated growth inhibition that was maximal at the earliest time point of 1 d and decreased exponentially with time during 10-12 d. The uptake of F-18-FDG per viable tumor volume was minimally affected by the treatment, whereas the F-18-FLT uptake decreased in correlation with the growth inhibition. Conclusion: The study suggests a prolonged action of the Hsp90 inhibitor that supports a once-per-week schedule. F-18-FLT is a suitable tracer for the monitoring of effect, and the F-18-FLT PET study might be performed within 3 d after dosing.
|
|
| 13. |
- Bergström, Mats
(author)
-
The Use of Microdosing in the Development of Small Organic and Protein Therapeutics
- 2017
-
In: Journal of Nuclear Medicine. - : SOC NUCLEAR MEDICINE INC. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 58:8, s. 1188-1195
-
Journal article (peer-reviewed)abstract
- Microdosing as a regulatory concept was introduced to facilitate exploratory studies in humans. The concept involves the use of very low doses of a radionuclide-labeled compound for imaging studies or for assessing plasma pharmacokinetics using equipment that has a highly sensitive readout. The supporting principle is that use of these low doses for a limited time in well-controlled, small populations will limit exposure and have a low risk of adverse effects. Microdosing regulations specify a reduced preclinical toxicology-assessment package in order to shorten the route to human studies and reduce its cost. However, for extrapolation to therapeutically relevant doses and plasma concentrations, there are specific aspects of the use of these low doses and low plasma concentrations that require special attention. These specific aspects are reviewed in this article, with separate attention being paid to small organic molecules and protein therapeutics. The indications for microdosing in drug development are discussed in terms of the 3 pillars of survival in drug development, the first of which is characterization of tissue distribution and access to the site of action; the second, engagement of the target; and the third, induction of tissue responses relevant to a therapeutic response.
|
|
| 14. |
- Boccalini, Cecilia, et al.
(author)
-
Early-Phase 18F-Florbetapir and 18F-Flutemetamol Images as Proxies of Brain Metabolism in a Memory Clinic Setting
- 2023
-
In: Journal of Nuclear Medicine. - : The Society of Nuclear Medicine and Molecular Imaging. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 64:2, s. 266-273
-
Journal article (peer-reviewed)abstract
- Alzheimer disease (AD) neuropathologic changes are 6-amyloid (A6) deposition, pathologic tau, and neurodegeneration. Dual-phase amy-loid PET might be able to evaluate A6 deposition and neurodegenera-tion with a single tracer injection. Early-phase amyloid PET scans provide a proxy for cerebral perfusion, which has shown good correla-tions with neural dysfunction measured through metabolic consump-tion, whereas the late frames depict amyloid distribution. Our study aimed to assess the comparability between early-phase amyloid PET scans and 18F-FDG PET brain topography at the individual level and their ability to discriminate patients. Methods: One hundred sixty-six subjects evaluated at the Geneva Memory Center, ranging from no cognitive impairment to mild cognitive impairment and dementia, underwent early-phase amyloid PET-using either 18F-florbetapir (eFBP) (n = 94) or 18F-flutemetamol (eFMM) (n = 72)-and 18F-FDG PET. A6 status was assessed. SUV ratios (SUVRs) were extracted to evaluate the correlation of eFBP/eFMM and their respective 18F-FDG PET scans. The single-subject procedure was applied to investigate hypometabolism and hypoperfusion maps and their spatial overlap by the Dice coefficient. Receiver-operating-characteristic analyses were performed to compare the discriminative power of eFBP/eFMM and 18F-FDG PET SUVR in AD-related meta-regions of interest between A6-negative healthy controls and cases in the AD continuum. Results: Positive correlations were found between eFBP/eFMM and 18F-FDG PET SUVR independently of A6 status and A6 radiotracer (R> 0.72, P< 0.001). eFBP/eFMM single-subject analysis revealed clusters of significant hypoperfusion with good correspondence to hypometabo-lism topographies, independently of the underlying neurodegenerative patterns. Both eFBP/eFMM and 18F-FDG PET SUVR significantly dis-criminated AD patients from controls in the AD-related meta-regions of interest (eFBP area under the curve [AUC], 0.888; eFMM AUC, 0.801), with 18F-FDG PET performing slightly better, although not sig-nificantly (all P values higher than 0.05), than others (18F-FDG AUC, 0.915 and 0.832 for subjects evaluated with eFBP and eFMM, respec-tively). Conclusion: The distribution of perfusion was comparable to that of metabolism at the single-subject level by parametric analysis, particularly in the presence of a high neurodegeneration burden. Our findings indicate that eFBP and eFMM imaging can replace 18F-FDG PET imaging, as they reveal typical neurodegenerative patterns or allow exclusion of the presence of neurodegeneration. The findings show cost-saving capacities of amyloid PET and support routine use of the modality for individual classification in clinical practice.
|
|
| 15. |
- Borges, João Batista, et al.
(author)
-
The Rediscovery of Galligas REPLY
- 2011
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 52:6, s. 1004-1004
-
Journal article (peer-reviewed)
|
|
| 16. |
- Borges, João Batista, et al.
(author)
-
Ventilation Distribution Studies Comparing Technegas and "Gallgas" Using (GaCl3)-Ga-68 as the Label
- 2011
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 52:2, s. 206-209
-
Journal article (peer-reviewed)abstract
- Ventilation distribution can be assessed by SPECT with Technegas. This study was undertaken in piglets with different degrees of ventilation inhomogeneity to compare PET using Ga-68-labeled pseudogas or "Gallgas" with Technegas. Methods: Twelve piglets were studied in 3 groups: control, lobar obstruction, and diffuse airway obstruction. Two more piglets were assessed for lung volume (functional residual capacity). Results: In controls, SPECT and PET images showed an even distribution of radioactivity. With lobar obstruction, the absence of ventilation of the obstructed lobe was visible with both techniques. In diffuse airway obstruction, SPECT images showed an even distribution of radioactivity, and PET images showed more varied radioactivity over the lung. Conclusion: PET provides detailed ventilation distribution images and a better appreciation of ventilation heterogeneity. Gallgas with PET is a promising new diagnostic tool for the assessment of ventilation distribution.
|
|
| 17. |
- Bragina, Olga, et al.
(author)
-
Phase I study of 99mTc-ADAPT6, a scaffold protein-based probe for visualization of HER2 expression in breast cancer
- 2021
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 62:4, s. 493-499
-
Journal article (peer-reviewed)abstract
- Radionuclide molecular imaging of human epidermal growth factor (HER2) expression may be helpful to stratify breast and gastroesophageal cancer patients for HER2-targeting therapies. ADAPTs (albumin-binding domain derived affinity proteins) are a new type of small (46-59 amino acids) proteins useful as probes for molecular imaging. The aim of this first-in-human study was to evaluate biodistribution, dosimetry, and safety of the HER2-specific 99mTc-ADAPT6.METHODS: Twenty-nine patients with primary breast cancerwere included. In 22 patients with HER2-positive (n = 11) or HER2-negative (n = 11) histopathology an intravenous injection with 385±125 MBq 99mTc-ADAPT6 was performed, randomized to an injected protein mass of either 500 µg (n = 11) or 1000 µg (n = 11). Planar scintigraphy followed by SPECT imaging was performed after 2, 4, 6 and 24 h. An additional cohort (n = 7) was injected with 165±29 MBq (injected protein mass 250 µg) and imaging was performed after 2 h only.RESULTS: Injections of 99mTc-ADAPT6 at all injected mass levels were well tolerated and not associated with adverse effects. 99mTc-ADAPT6 cleared rapidly from blood and most other tissues. The normal organs with the highest accumulation were kidney, liver and lung. Effective doses were 0.009±0.002 and 0.010±0.003 mSv/MBq for injected protein masses of 500 and 1000 µg, respectively. Injection of 500 µg resulted in excellent discrimination between HER2-positive and HER2-negative tumors already 2 h after injection (tumor-to-contralateral breast ratio was 37±19 vs 5±2, p<0.01). The tumor-to-contralateral breast ratios for HER2-positive tumors were significantly (p<0.05) higher for injected mass of 500 µg than for both 250 and 1000 µg.CONCLUSION: Injections of 99mTc-ADAPT6 are safe and associated with low absorbed and effective doses. Protein dose of 500 µg is preferable for discrimination between tumors with high and low expression of HER2. Further studies are justified to evaluate if 99mTc-ADAPT6 can be used as an imaging probe for stratification of patients for HER2-targeting therapy in the areas where PET imaging is not readily available.
|
|
| 18. |
- Bragina, Olga, et al.
(author)
-
Phase I Trial of 99mTc-(HE)3-G3, a DARPin-Based Probe for Imaging of HER2 Expression in Breast Cancer
- 2022
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 63:4, s. 528-535
-
Journal article (peer-reviewed)abstract
- Radionuclide molecular imaging of human epidermal growth factor receptor type 2 (HER2) expression may enable a noninvasive discrimination between HER2-positive and HER2-negative breast cancers for stratification of patients for HER2-targeted treatments. DARPin (designed ankyrin repeat proteins) G3 is a small (molecular weight, 14 kDa) scaffold protein with picomolar affinity to HER2. The aim of this first-in-humans study was to evaluate the safety, biodistribution, and dosimetry of 99mTc-(HE)3-G3.Methods: Three cohorts of patients with primary breast cancer (each including at least 4 patients with HER2-negative and 5 patients with HER2-positive tumors) were injected with 1,000, 2,000, or 3,000 μg of 99mTc-(HE)3-G3 (287 ± 170 MBq). Whole-body planar imaging followed by SPECT was performed at 2, 4, 6, and 24 h after injection. Vital signs and possible side effects were monitored during imaging and up to 7 d after injection.Results: All injections were well tolerated. No side effects were observed. The results of blood and urine analyses did not differ before and after studies. 99mTc-(HE)3-G3 cleared rapidly from the blood. The highest uptake was detected in the kidneys and liver followed by the lungs, breasts, and small intestinal content. The hepatic uptake after injection of 2,000 or 3,000 μg was significantly (P < 0.05) lower than the uptake after injection of 1,000 μg. Effective doses did not differ significantly between cohorts (average, 0.011 ± 0.004 mSv/MBq). Tumor–to–contralateral site ratios for HER-positive tumors were significantly (P < 0.05) higher than for HER2-negative at 2 and 4 h after injection.Conclusion: Imaging of HER2 expression using 99mTc-(HE)3-G3 is safe and well tolerated and provides a low absorbed dose burden on patients. This imaging enables discernment of HER2-positive and HER2-negative breast cancer. Phase I study data justify further clinical development of 99mTc-(HE)3-G3.
|
|
| 19. |
|
|
| 20. |
- Bäck, Tom, 1964, et al.
(author)
-
The alpha-camera: a quantitative digital autoradiography technique using a charge-coupled device for ex vivo high-resolution bioimaging of alpha-particles.
- 2010
-
In: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 1535-5667. ; 51:10, s. 1616-23
-
Journal article (peer-reviewed)abstract
- Bioconjugates used in internal radiotherapy exhibit heterogeneous distributions in organs and tumors, implying a risk of nonuniform dose distribution in therapeutic applications using α-particle emitters. Tools are required that provide data on the activity distribution for estimation of absorbed dose on a suborgan level. The α-camera is a quantitative imaging technique developed to detect α-particles in tissues ex vivo. The aim of this study was to evaluate the characteristics of this imaging system and to exemplify its potential use in the development of α-radioimmunotherapy.
|
|
| 21. |
- Carter, Stephen F., et al.
(author)
-
Evidence for Astrocytosis in Prodromal Alzheimer Disease Provided by C-11-Deuterium-L-Deprenyl : A Multitracer PET Paradigm Combining C-11-Pittsburgh Compound B and F-18-FDG
- 2012
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 53:1, s. 37-46
-
Journal article (peer-reviewed)abstract
- Astrocytes colocalize with fibrillar amyloid-beta (A beta) plaques in postmortem Alzheimer disease (AD) brain tissue. It is therefore of great interest to develop a PET tracer for visualizing astrocytes in vivo, enabling the study of the regional distribution of both astrocytes and fibrillar A beta. A multitracer PET investigation was conducted for patients with mild cognitive impairment (MCI), patients with mild AD, and healthy controls using C-11-deuterium-L-deprenyl (C-11-DED) to measure monoamine oxidase B located in astrocytes. Along with C-11-DED PET, C-11-Pittsburgh compound B (C-11-PIB; fibrillar A beta deposition), F-18-FDG (glucose metabolism), T1 MRI, cerebrospinal fluid, and neuropsychologic data were acquired from the patients. Methods: C-11-DED PET was performed in MCI patients (n = 8; mean age 6 SD, 62.6 +/- 7.5 y; mean Mini Mental State Examination, 27.5 +/- 2.1), AD patients (n = 7; mean age, 65.1 +/- 6.3 y; mean Mini Mental State Examination, 24.4 +/- 5.7), and healthy age-matched controls (n = 14; mean age, 64.7 +/- 3.6 y). A modified reference Patlak model, with cerebellar gray matter as a reference, was chosen for kinetic analysis of the C-11-DED data. C-11-DED data from 20 to 60 min were analyzed using a digital brain atlas. Mean regional F-18-FDG uptake and C-11-PIB retention were calculated for each patient, with cerebellar gray matter as a reference. Results: ANOVA analysis of the regional C-11-DED binding data revealed a significant group effect in the bilateral frontal and bilateral parietal cortices related to increased binding in the MCI patients. All patients, except 3 with MCI, showed high C-11-PIB retention. Increased C-11-DED binding in most cortical and subcortical regions was observed in MCI C-11-PIB+ patients relative to controls, MCI C-11-PIB (negative) patients, and AD patients. No regional correlations were found between the 3 PET tracers. Conclusion: Increased C-11-DED binding throughout the brain of the MCI C-11-PIB+ patients potentially suggests that astrocytosis is an early phenomenon in AD development.
|
|
| 22. |
- Chouin, Nicolas, et al.
(author)
-
Ex Vivo Activity Quantification in Micrometastases at the Cellular Scale Using the α-Camera Technique.
- 2013
-
In: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 1535-5667. ; 54:8, s. 1347-1353
-
Journal article (peer-reviewed)abstract
- Targeted α-therapy (TAT) appears to be an ideal therapeutic technique for eliminating malignant circulating, minimal residual, or micrometastatic cells. These types of malignancies are typically infraclinical, complicating the evaluation of potential treatments. This study presents a method of ex vivo activity quantification with an α-camera device, allowing measurement of the activity taken up by tumor cells in biologic structures a few tens of microns. METHODS: We examined micrometastases from a murine model of ovarian carcinoma after injection of a radioimmunoconjugate labeled with (211)At for TAT. At different time points, biologic samples were excised and cryosectioned. The activity level and the number of tumor cells were determined by combined information from 2 adjacent sections: one exposed to the α-camera and the other stained with hematoxylin and eosin. The time-activity curves for tumor cell clusters, comprising fewer than 10 cells, were derived for 2 different injected activities (6 and 1 MBq). RESULTS: High uptake and good retention of the radioimmunoconjugate were observed at the surface of tumor cells. Dosimetric calculations based on the measured time-integrated activity indicated that for an injected activity of 1 MBq, isolated tumor cells received at least 12 Gy. In larger micrometastases (≤100 μm in diameter), the activity uptake per cell was lower, possibly because of hindered penetration of radiolabeled antibodies; however, the mean absorbed dose delivered to tumor cells was above 30 Gy, due to cross-fire irradiation. CONCLUSION: Using the α-camera, we developed a method of ex vivo activity quantification at the cellular scale, which was further applied to characterize the behavior of a radiolabeled antibody administered in vivo against ovarian carcinoma. This study demonstrated a reliable measurement of activity. This method of activity quantification, based on experimentally measured data, is expected to improve the relevance of small-scale dosimetry studies and thus to accelerate the optimization of TAT.
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
- Danad, I., et al.
(author)
-
Hybrid imaging using quantitative H2 15O PET and CT-based coronary angiography for the detection of coronary artery disease
- 2013
-
In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 54:1, s. 55-63
-
Journal article (peer-reviewed)abstract
- Hybrid imaging using PET in conjunction with CT-based coronary angiography (PET/CTCA) enables near-simultaneous quantification of myocardial blood flow (MBF) and anatomical evaluation of coronary arteries. CTCA is an excellent imaging modality to rule out obstructive coronary artery disease (CAD), but functional assessment is warranted in the presence of a CTCA-observed stenosis because the specificity of CTCA is relatively low. Quantitative H 2 15O PET/CTCA may yield complementary information and enhance diagnostic accuracy. The purpose of this study was to evaluate the diagnostic accuracy of quantitative H2 15O PET/CTCA in a clinical cohort of patients with suspected CAD who underwent both cardiac H 2 15O PET/CTCA and invasive coronary angiography (ICA). In addition, this study aimed to evaluate and compare the accuracy of hyperemic MBF versus coronary flow reserve (CFR). Methods: Patients (n = 120; mean age ± SD, 61 ± 10 y; 77 men and 43 women) with a predominantly intermediate pretest likelihood for CAD underwent both quantitative H 2 15O PET/CTCA and ICA. A ≥50% stenosis at ICA or a fractional flow reserve ≤ 0.80 was considered significant. Results: Obstructive CAD was diagnosed in 49 of 120 patients (41%). The diagnostic accuracy of hyperemic MBF was significantly higher than CFR (80% vs. 68%, respectively, P = 0.02), with optimal cutoff values of 1.86 mL/min/g and 2.30, respectively. On a per-patient basis, the sensitivity, specificity, negative predictive value, and positive predictive value of CTCA were 100%, 34%, 100%, and 51%, respectively, as compared with 76%, 83%, 83%, and 76%, respectively, for quantitative hyperemic MBF PET. Quantitative H2 15O PET/CTCA reduced the number of false-positive CTCA studies from 47 to 6, although 12 of 49 true-positive CTCAs were incorrectly reclassified as false-negative hybrid scans on the basis of (presumably) sufficient hyperemic MBF. Compared with CTCA (61%) or H2 15O PET (80%) alone (both P < 0.05), the hybrid approach significantly improved diagnostic accuracy (85%). Conclusion: The diagnostic accuracy of quantitative H 2 15O PET/CTCA is superior to either H2 15O PET or CTCA alone for the detection of clinically significant CAD. Hyperemic MBF was more accurate than CFR, implying that a single measurement of MBF in diagnostic protocols may suffice.
|
|
