The Race for Hydroxamate-Based Zirconium-89 Chelators

Metallic radionuclides conjugated to biological vectors via an appropriate chelator are employed in nuclear medicine for the diagnosis (imaging) and radiotherapy of diseases. For the application of radiolabeled antibodies using positron emission tomography (immunoPET), zirconium-89 has gained increasing interest over the last decades as its physical properties (t1/2 = 78.4 h, 22.6% β+ decay) match well with the slow pharmacokinetics of antibodies (tbiol. = days to weeks) allowing for late time point imaging. The most commonly used chelator for 89Zr in this context is desferrioxamine (DFO). However, it has been shown in preclinical studies that the hexadentate DFO ligand does not provide 89Zr-complexes of sufficient stability in vivo and unspecific uptake of the osteophilic radiometal in bones is observed. For clinical applications, this might be of concern not only because of an unnecessary dose to the patient but also an increased background signal. As a consequence, next generation chelators based on hydroxamate scaffolds for more stable coordination of 89Zr have been developed by different research groups. In this review, we describe the progress in this research field until end of 2020, including promising examples of new candidates of chelators currently in advanced stages for clinical translation that outrun the performance of the current gold standard DFO.

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Equivalent tumor detection for early and late FAPI-46 PET acquisition

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-021-05266-7 ◽

2021 ◽

Author(s):

J. Ferdinandus ◽

L. Kessler ◽

N. Hirmas ◽

M. Trajkovic-Arsic ◽

R. Hamacher ◽

...

Keyword(s):

Early Time ◽

Tumor Detection ◽

University Hospital ◽

Late Time ◽

Early Time Point ◽

Positron Emission ◽

Organ Uptake ◽

Significant Difference ◽

Late Time Point ◽

Time Point

Abstract Introduction Positron emission tomography (PET) using small ligands of the fibroblast activation protein (FAP) was recently introduced. However, optimal uptake time has not been defined yet. Here, we systematically compare early (~ 10 min p.i.) and late (~ 60 min p.i.) FAPI-46 imaging in patients with various types of cancer. Methods This is a retrospective single-institutional study. Imaging was performed at the Essen University Hospital, Germany. A total of 69 patients who underwent dual time-point imaging for either restaging (n = 52, 75%) or staging (n = 17, 25%) of cancer were included. Patients underwent PET with two acquisitions: early (mean 11 min, SD 4) and late (mean 66 min, SD 9). Mean injected activity was 148 MBq (SD 33). Results In total, 400 lesions were detected in 69 patients. Two of 400 (0.5%) lesions were only seen in early time-point imaging but not in late time-point imaging. On a per-patient level, there was no significant difference between SUVmax of hottest tumor lesions (Wilcoxon: P = 0.73). Organ uptake demonstrated significant early to late decrease in SUVmean (average ∆SUVmean: − 0.48, − 0.14, − 0.27 for gluteus, liver, and mediastinum, respectively; Wilcoxon: P < 0.001). On a per-lesion basis, a slight increase of SUVmax was observed (average ∆SUVmax: + 0.4, Wilcoxon: P = 0.03). Conclusion In conclusion, early (~ 10 min p.i.) versus late (~ 60 min p.i.) FAPI-46 imaging resulted in equivalent lesion uptake and tumor detection. For improved feasibility and scan volume, we implement early FAPI-46 PET in future clinical and research protocols.

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Exploiting the Concept of Multivalency with 68Ga- and 89Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

Contrast Media & Molecular Imaging ◽

10.1155/2018/3171794 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Dominik Summer ◽

Christine Rangger ◽

Maximilian Klingler ◽

Peter Laverman ◽

Gerben M. Franssen ◽

...

Keyword(s):

Metabolic Stability ◽

Cell Uptake ◽

Late Time ◽

Biodistribution Studies ◽

Imaging Probes ◽

Gallium 68 ◽

Late Time Point ◽

Time Point

Cholecystokinin-2 receptors (CCK2R) are overexpressed in a variety of malignant diseases and therefore have gained certain attention for peptide receptor radionuclide imaging. Among extensive approaches to improve pharmacokinetics and metabolic stability of minigastrin (MG) based radioligands, the concept of multivalency for enhanced tumour targeting has not been investigated extensively. We therefore utilized fusarinine C (FSC) as chelating scaffold for novel mono-, di-, and trimeric bioconjugates for targeting CCK2R expression. FSC-based imaging probes were radiolabelled with positron emitting radionuclides (gallium-68 and zirconium-89) and characterized in vitro (log⁡D, IC50, and cell uptake) and in vivo (metabolic stability in BALB/c mice, biodistribution profile, and microPET/CT imaging in A431-CCK2R/A431-mock tumour xenografted BALB/c nude mice). Improved targeting did not fully correlate with the grade of multimerization. The divalent probe showed higher receptor affinity and increased CCK2R mediated cell uptake while the trimer remained comparable to the monomer. In vivo biodistribution studies 1 h after administration of the 68Ga-labelled radioligands confirmed this trend, but imaging at late time point (24 h) with 89Zr-labelled counterparts showed a clearly enhanced imaging contrast of the trimeric probe compared to the mono- and dimer. Furthermore, in vivo stability studies showed a higher metabolic stability for multimeric probes compared to the monomeric bioconjugate. In summary, we could show that FSC can be utilized as suitable scaffold for novel mono- and multivalent imaging probes for CCK2R-related malignancies with partly improved targeting properties for multivalent conjugates. The increased tumour accumulation of the trimer 24 h postinjection (p.i.) can be explained by slower clearance and increased metabolic stability of multimeric conjugates.

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Echocardiographic Myocardial Strain Analysis Describes Subclinical Cardiac Dysfunction after Craniospinal Irradiation in Pediatric and Young Adult Patients with Central Nervous System Tumors

10.21203/rs.3.rs-121700/v1 ◽

2020 ◽

Author(s):

Thomas D Ryan ◽

Hugo R. Martinez ◽

Ralph Salloum ◽

Erin Wright ◽

Lauren Bueche ◽

...

Keyword(s):

Central Nervous System ◽

Cardiac Dysfunction ◽

Myocardial Strain ◽

Strain Analysis ◽

Late Time ◽

Systolic Strain ◽

Peak Systolic Strain ◽

Myocardial Strain Analysis ◽

Late Time Point ◽

Time Point

Abstract Background: Craniospinal irradiation (CSI) is part of the treatment of central nervous system (CNS) tumors and is associated with cardiovascular disease in adults. Global myocardial strain analysis including longitudinal peak systolic strain (GLS), circumferential peak systolic strain (GCS) and radial peak systolic strain (GRS) can reveal subclinical cardiac dysfunction.Methods: Retrospective, single-center study in patients managed with CSI vs. age-matched controls. Clinical data and echocardiography, including myocardial strain analysis, were collected at early (<12 months) and late ( 12 months) after completion of CSI.Results: Echocardiograms were available in 20 early and 34 late patients. Patients at the late time point were older (21.7±10.4 vs. 13.3 9.6 years), and further out from CSI (13.1±8.8 vs. 0.2±0.3 years). Standard echocardiographic parameters were normal for all subjects. For the early time, CSI vs. control: GLS was -16.8 3.6% vs. -21.3 4.0% (p=0.0002), GCS was -22.5 5.2% vs. -21.3 3.4% (p=0.28), and GRS was 21.8 11.0% vs. 26.9 7.7% (p=0.07). At the late time point, CSI vs. control: GLS was -16.2 5.4% vs. -21.6 3.7% (p<0.0001), GCS was -20.9 6.8% vs. -21.9 3.5% (p=0.42), and GRS was 22.5 10.0% vs. 27.3 8.3% (p=0.03). Radiation type (proton vs. photon), and radiation dose (<30 Gy vs. 30 Gy) did not impact any parameter.Conclusions: Subclinical cardiac systolic dysfunction by GLS is present both early and late after CSI. These results argue for inclusion of baseline cardiovascular assessment and early initiation of longitudinal follow-up post CSI.

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Preclinical Evaluation of the Copper-64 Labeled GRPR-Antagonist RM26 in Comparison with the Cobalt-55 Labeled Counterpart for PET-Imaging of Prostate Cancer

Molecules ◽

10.3390/molecules25245993 ◽

2020 ◽

Vol 25 (24) ◽

pp. 5993

Author(s):

Christina Baun ◽

Bogdan Mitran ◽

Sara S. Rinne ◽

Johan H. Dam ◽

Birgitte B. Olsen ◽

...

Keyword(s):

Pet Imaging ◽

Late Time ◽

Vitro Binding ◽

Pet Ct ◽

Liver And Pancreas ◽

Prostate Cancers ◽

Grpr Antagonist ◽

Late Time Point

Gastrin-releasing peptide receptor (GRPR) is overexpressed in the majority of prostate cancers. This study aimed to investigate the potential of 64Cu (radionuclide for late time-point PET-imaging) for imaging of GRPR expression using NOTA-PEG2-RM26 and NODAGA-PEG2-RM26. Methods: NOTA/NODAGA-PEG2-RM26 were labeled with 64Cu and evaluated in GRPR-expressing PC-3 cells. Biodistribution of [64Cu]Cu-NOTA/NODAGA-PEG2-RM26 was studied in PC-3 xenografted mice and compared to the biodistribution of [57Co]Co-NOTA/NODAGA-PEG2-RM26 at 3 and 24 h p.i. Preclinical PET/CT imaging was performed in tumor-bearing mice. NOTA/NODAGA-PEG2-RM26 were stably labeled with 64Cu with quantitative yields. In vitro, binding of [64Cu]Cu-NOTA/NODAGA-PEG2-RM26 was rapid and GRPR-specific with slow internalization. In vivo, [64Cu]Cu-NOTA/NODAGA-PEG2-RM26 bound specifically to GRPR-expressing tumors with fast clearance from blood and normal organs and displayed generally comparable biodistribution profiles to [57Co]Co-NOTA/NODAGA-PEG2-RM26; tumor uptake exceeded normal tissue uptake 3 h p.i.. Tumor-to-organ ratios did not increase significantly with time. [64Cu]Cu-NOTA-PEG2-RM26 had a significantly higher liver and pancreas uptake compared to other agents. 57Co-labeled radioconjugates showed overall higher tumor-to-non-tumor ratios, compared to the 64Cu-labeled counterparts. [64Cu]Cu-NOTA/NODAGA-PEG2-RM26 was able to visualize GRPR-expression in a murine PC model using PET. However, [55/57Co]Co-NOTA/NODAGA-PEG2-RM26 provided better in vivo stability and overall higher tumor-to-non-tumor ratios compared with the 64Cu-labeled conjugates.

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Quantitative Measurement of Cerebral Acetylcholinesterase Using [11C]physostigmine and Positron Emission Tomography

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200102000-00003 ◽

2001 ◽

Vol 21 (2) ◽

pp. 114-131 ◽

Cited By ~ 14

Author(s):

Gunnar Blomqvist ◽

Bertrand Tavitian ◽

Sabina Pappata ◽

Christian Crouzel ◽

Antoinette Jobert ◽

...

Keyword(s):

Positron Emission Tomography ◽

White Matter ◽

Good Description ◽

Acetylcholinesterase Inhibitor ◽

Emission Tomography ◽

Late Time ◽

Reference Tissue ◽

Positron Emission ◽

Simplified Reference Tissue Model

[11C]physostigmine, an acetylcholinesterase inhibitor, has been shown to be a promising positron emission tomography ligand to quantify the cerebral concentration of the enzyme in animals and humans in vivo. Here, a quantitative and noninvasive method to measure the regional acetylcholinesterase concentration in the brain is presented. The method is based on the observation that the ratio between regions rich in acetylcholinesterase and white matter, a region almost entirely deprived of this enzyme, was found to become approximately constant after 20 to 30 minutes, suggesting that at late time points the uptake mainly contains information about the distribution volume. Taking the white matter as the reference region, a simplified reference tissue model, with effectively one reversible tissue compartment and three parameters, was found to give a good description of the data in baboons. One of these parameters, the ratio between the total distribution volumes in the target and reference regions, showed a satisfactory correlation with the acetylcholinesterase concentration measured postmortem in two baboon brains. Eight healthy male subjects were also analyzed and the regional enzyme concentrations obtained again showed a good correlation with the known acetylcholinesterase concentrations measured in postmortem studies of human brain.

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Naturally arising CD4+CD25+ regulatory T cells suppress the expansion of colitogenic CD4+CD44highCD62L− effector memory T cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00429.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. G1051-G1058 ◽

Cited By ~ 11

Author(s):

T. Kanai ◽

K. Tanimoto ◽

Y. Nemoto ◽

R. Fujii ◽

S. Makita ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Effector Memory ◽

Late Time ◽

Suppressive Activity ◽

Time Point

Naturally arising CD4+CD25+ regulatory T (TR) cells have been shown to prevent and cure murine T cell-mediated colitis. However, their exact mechanism of controlling colitogenic memory CD4+ T cells in in vivo systems excluding the initial process of naive T cell activation and differentiation has not been examined to date. Using the colitogenic effector memory (TEM) CD4+ cell-mediated colitis model induced by adoptive transfer of colitogenic CD4+CD44highCD62L− lamina propria (LP) T cells obtained from colitic CD4+CD45RBhigh T cell-transferred mice, we have shown in the present study that CD4+CD25+ TR cells are able not only to suppress the development of colitis, Th1 cytokine production, and the expansion of colitogenic LP CD4+ TEM cells but also to expand these cells by themselves extensively in vivo. An in vitro coculture assay revealed that CD4+CD25+ TR cells proliferated in the presence of IL-2-producing colitogenic LP CD4+ TEM cells at the early time point (48 h after culture), followed by the acquisition of suppressive activity at the late time point (96 h after culture). Collectively, these data suggest the distinct timing of the IL-2-dependent expansion of CD4+CD25+ TR cells and the their suppressive activity on colitogenic LP CD4+ TEM cells.

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Bronchial reactivity of healthy subjects: 18–20 h postexposure to ozone

Journal of Applied Physiology ◽

10.1152/jappl.2000.89.5.1804 ◽

2000 ◽

Vol 89 (5) ◽

pp. 1804-1810 ◽

Cited By ~ 56

Author(s):

W. Michael Foster ◽

Robert H. Brown ◽

Kristin Macri ◽

Clifford S. Mitchell

Keyword(s):

Healthy Subjects ◽

Ambient Air ◽

Respiratory Morbidity ◽

Late Time ◽

Late Period ◽

Bronchial Reactivity ◽

Markers Of Inflammation ◽

Late Time Point ◽

Ambient Levels ◽

Time Point

Exposure of humans to ambient levels of ozone (O3) causes inflammatory changes within lung tissues. These changes have been reported for the “initial” (1- to 3-h) and “late” (18- to 20-h) postexposure periods. We hypothesized that at the late period, when protein and cellular markers of inflammation at the airway surface remain abnormal and the integrity of the epithelial barrier is compromised, bronchial reactivity would be increased. To test this, we measured airway responsiveness to cumulative doses of methacholine (MCh) aerosol in healthy subjects 19 ± 1 h after a single exposure to O3 (130 min at ambient levels between 120 and 240 parts/billion and alternate periods of rest and moderate exercise) or filtered air. Exposures were conducted at two temperatures: mild (22°C) and moderate (30°C). At the late period, bronchial reactivity to MCh increased, i.e., interpolated dose of MCh leading to a 50% fall in specific airway conductance (PC50) was less after O3 than after filtered air. PC50 for O3 at 22°C was 27 mg/ml (20% less than the PC50 after filtered air), and for O3 at 30°C it was 19 mg/ml (70% less than the PC50 after filtered air). The forced expiratory volume in 1 s (FEV1) at the late time point after O3 was slightly but significantly reduced (2.3%) from the preexposure level. There was no relationship found between the functional changes observed early after exposure to O3 and subsequent changes in bronchial reactivity or FEV1 at the late time point. These results suggest that bronchial reactivity is significantly altered ∼1 day after O3; this injury may contribute to the respiratory morbidity that is observed 1–2 days after an episode of ambient air pollution.

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64Cu-DOTATATE Positron Emission Tomography (PET) of Borrelia Burgdorferi Infection: In Vivo Imaging of Macrophages in Experimental Model of Lyme Arthritis

Diagnostics ◽

10.3390/diagnostics10100790 ◽

2020 ◽

Vol 10 (10) ◽

pp. 790

Author(s):

Anne Skovsbo Clausen ◽

Mathilde Ørbæk ◽

Regitze Renee Pedersen ◽

Peter Oestrup Jensen ◽

Anne-Mette Lebech ◽

...

Keyword(s):

Borrelia Burgdorferi ◽

Plasma Levels ◽

Lyme Arthritis ◽

Borrelia Burgdorferi Sensu Lato ◽

Late Time ◽

Macrophage Marker ◽

Positron Emission ◽

Pet Ct ◽

Significant Difference

Macrophages play a key role in the inflammatory response in Lyme arthritis (LA) and could be a target for diagnosing and monitoring active Borrelia burgdorferi sensu lato (Bb) infection. Therefore, we evaluated the potential of macrophage imaging using 64Cu-DOTATATE PET/CT for detection of Bb activity in a murine model of LA. LA was established in C3H/HeNRj mice infected with Bb B31 strain ML23 pBBE22luc. Bioluminescence imaging was performed to detect migration of spirochetes and inflammatory phagocytes to the joints. Three weeks post-infection 64Cu-DOTATATE PET/CT imaging was performed at an early (3 h) and late (48 h) time point. Plasma levels of a systemic macrophage marker in plasma CD163 were measured. 64Cu-DOTATATE uptake in infected joints was increased at the early (p < 0.0001) and late time points (p = 0.0005) compared with uptake in non-infected controls. No significant difference in plasma levels of CD163 was measured. 64Cu-DOTATATE PET allows for in vivo detection and quantification of LA locally in the joints through non-invasive visualization of macrophages. In contrast, measurement of a systemic macrophage marker in plasma, CD163, did not allow to detect disease. We suggest that 64Cu-DOTATATE PET could become a valuable diagnostic tool for in situ detection of Bb infection-related inflammation.

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Effects of Mechanical Compression on Chondrogenesis of Human Synovium-Derived Mesenchymal Stem Cells in Agarose Hydrogel

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.697281 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuxiang Ge ◽

Yixuan Li ◽

Zixu Wang ◽

Lan Li ◽

Huajian Teng ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Chondrogenic Differentiation ◽

Dynamic Compression ◽

Early Time ◽

Late Time ◽

Mechanical Compression ◽

Early Time Point ◽

Late Time Point ◽

Time Point

Mechanical compression is a double-edged sword for cartilage remodeling, and the effect of mechanical compression on chondrogenic differentiation still remains elusive to date. Herein, we investigate the effect of mechanical dynamic compression on the chondrogenic differentiation of human synovium-derived mesenchymal stem cells (SMSCs). To this aim, SMSCs encapsulated in agarose hydrogels were cultured in chondrogenic-induced medium with or without dynamic compression. Dynamic compression was applied at either early time-point (day 1) or late time-point (day 21) during chondrogenic induction period. We found that dynamic compression initiated at early time-point downregulated the expression level of chondrocyte-specific markers as well as hypertrophy-specific markers compared with unloaded control. On the contrary, dynamic compression applied at late time-point not only enhanced the levels of cartilage matrix gene expression, but also suppressed the hypertrophic development of SMSCs compared with unloaded controls. Taken together, our findings suggest that dynamic mechanical compression loading not only promotes chondrogenic differentiation of SMSCs, but also plays a vital role in the maintenance of cartilage phenotype, and our findings also provide an experimental guide for stem cell-based cartilage repair and regeneration.

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Can a Biohybrid Patch Salvage Ventricular Function at a Late Time Point in the Post-Infarction Remodeling Process?

JACC Basic to Translational Science ◽

10.1016/j.jacbts.2021.01.004 ◽

2021 ◽

Author(s):

Lindemberg M. Silveira-Filho ◽

Garrett N. Coyan ◽

Arianna Adamo ◽

Samuel K. Luketich ◽

Giorgio Menallo ◽

...

Keyword(s):

Ventricular Function ◽

Late Time ◽

Late Time Point ◽

Time Point

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