Preclinical assessment of [68Ga]Ga-Cell Death Indicator (CDI): a novel hsp90 ligand for positron emission tomography of cell death

Background: 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) when conjugated with a bifunctional chelator 2,2'-(7-(1-carboxy-4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODAGA) (hereafter referred to as Cell Death Indicator [CDI]), enters dead and dying cells and binds to 90kDa heat shock proteins (hsp90). Objective: This study assesses stability, biodistribution, imaging, and radiation dosimetry of [68Ga]Ga-CDI for positron emission tomography (PET). Methods: Preparation of [68Ga]Ga-CDI was performed as previously described. Product stability and stability in plasma were assessed using high-performance liquid chromatography. Biodistribution and imaging were conducted in ten healthy male Lewis rats at 1 and 2 h following intravenous [68Ga]Ga-CDI injection. Human radiation dosimetry was estimated by extrapolation for a standard reference man and calculated with OLINDA/EXM 1.1. Results: Radiochemical purity of [68Ga]Ga-CDI averaged 93.8% in the product and 86.7% in plasma at 4 h post-synthesis. The highest concentration of [68Ga]Ga-CDI is observed in the kidneys; [68Ga]Ga-CDI is excreted in the urine, and mean retained activity was 32.4% and 21.4% at 1 and 2 h post-injection. Lower concentrations of [68Ga]Ga-CDI were present in the small bowel and liver. PET CT was concordant and additionally demonstrated focal growth plate uptake. The effective dose for [68Ga]Ga-CDI is 2.16E-02 mSv/MBq, and the urinary bladder wall received the highest dose (1.65E-02mSv/Mbq). Conclusions: [68Ga]Ga-CDI is stable and has favourable biodistribution, imaging, and radiation dosimetry for imaging of dead and dying cells. Human studies are underway.

Download Full-text

[18F]FEDAC translocator protein positron emission tomography–computed tomography for early detection of mitochondrial dysfunction secondary to myocardial ischemia

Annals of Nuclear Medicine ◽

10.1007/s12149-021-01630-7 ◽

2021 ◽

Author(s):

Rui Luo ◽

Lei Wang ◽

Fei Ye ◽

Yan-Rong Wang ◽

Wei Fang ◽

...

Keyword(s):

Computed Tomography ◽

Positron Emission Tomography ◽

Early Detection ◽

Myocardial Ischemia ◽

Mitochondrial Dysfunction ◽

High Performance ◽

Dynamic Imaging ◽

Translocator Protein ◽

Emission Tomography ◽

Positron Emission

Abstract Background This study aimed to evaluate the biodistribution and kinetics of [18F]FEDAC targeting the translocator protein TSPO in the myocardium, and to explore its use for the identification of mitochondrial dysfunction. We also assessed the feasibility of [18F]FEDAC for the early detection of mitochondrial dysfunction associated with myocardial ischemia (MI). Methods The radiochemical purity and stability of [18F]FEDAC were analyzed by radio-high-performance liquid chromatography (radio-HPLC). Its biodistribution and kinetics were evaluated by dissection and dynamic imaging using micro-positron emission tomography–computed tomography (micro-PET–CT) in healthy mice. [18F]FEDAC was also applied in an MI rat model and in sham-operated controls. Mitochondrial changes were observed by immunohistochemical staining and electron microscopy. Results Radioactivity levels (%ID/g) in the myocardium in normal mice, determined by [18F]FEDAC, were 8.32 ± 0.80 at 5 min and 2.40 ± 0.10 at 60 min. PET showed significantly decreased uptake by injured cardiac tissue in MI rats, with maximal normal-to-ischemic uptake ratios of 10.47 ± 3.03 (1.5 min) and 3.92 ± 1.12 (27.5 min) (P = 0.025). Immunohistochemistry confirmed that TSPO expression was decreased in MI rats. Mitochondrial ultrastructure demonstrated significant swelling and permeability. Conclusion [18F]FEDAC uptake is reduced in the injured myocardium, consistent with mitochondrial dysfunction. These results may provide new evidence to aid the early detection of mitochondrial dysfunction associated with myocardial ischemic injury.

Download Full-text

Evaluation of Various Scintillator Materials in Radiation Detector Design for Positron Emission Tomography (PET)

Crystals ◽

10.3390/cryst10100869 ◽

2020 ◽

Vol 10 (10) ◽

pp. 869

Author(s):

Siwei Xie ◽

Xi Zhang ◽

Yibin Zhang ◽

Gaoyang Ying ◽

Qiu Huang ◽

...

Keyword(s):

Positron Emission Tomography ◽

High Performance ◽

Radiation Detector ◽

Experimental Studies ◽

Light Output ◽

Radiation Detectors ◽

Emission Tomography ◽

Timing Resolution ◽

Positron Emission ◽

Co Doped

The performance of radiation detectors used in positron-emission tomography (PET) is determined by the intrinsic properties of the scintillators, the geometry and surface treatment of the scintillator crystals and the electrical and optical characteristics of the photosensors. Experimental studies were performed to assess the timing resolution and energy resolution of detectors constructed with samples of different scintillator materials (LaBr3, CeBr3, LFS, LSO, LYSO: Ce, Ca and GAGG) that were fabricated into different shapes with various surface treatments. The saturation correction of SiPMs was applied for tested detectors based on a Tracepro simulation. Overall, we tested 28 pairs of different forms of scintillators to determine the one with the best CTR and light output. Two common high-performance silicon photomultipliers (SiPMs) provided by SensL (J-series, 6 mm) or AdvanSiD (NUV, 6 mm) were used for photodetectors. The PET detector constructed with 6 mm CeBr3 cubes achieved the best CTR with a FWHM of 74 ps. The 4 mm co-doped LYSO: Ce, Ca pyramid crystals achieved 88.1 ps FWHM CTR. The 2 mm, 4 mm and 6 mm 0.2% Ce, 0.1% Ca co-doped LYSO cubes achieved 95.6 ps, 106 ps and 129 ps FWHM CTR, respectively. The scintillator crystals with unpolished surfaces had better timing than those with polished surfaces. The timing resolution was also improved by using certain geometric factors, such as a pyramid shape, to improve light transportation in the scintillator crystals.

Download Full-text

Late onset of nivolumab-induced severe gastroduodenitis and cholangitis in a patient with stage IV melanoma

Immunotherapy ◽

10.2217/imt-2019-0077 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1005-1013 ◽

Cited By ~ 6

Author(s):

Andreea Cǎlugǎreanu ◽

Pierre Rompteaux ◽

Gérôme Bohelay ◽

Lucas Goldfarb ◽

Vincent Barrau ◽

...

Keyword(s):

Computed Tomography ◽

Positron Emission Tomography ◽

Immune Response ◽

Cell Death ◽

Late Onset ◽

Stage Iv ◽

Emission Tomography ◽

Immune Checkpoints ◽

Cell Immune Response ◽

Positron Emission

Antiprogramed cell death-1 protein agents represent a therapeutic approach based on stimulating the host’s immune response through blockade of immune checkpoints, inhibitory pathways that dampen the physiological peripheral T-cell immune response and are essential for maintaining self-tolerance. We describe the late onset of severe gastroduodenitis and cholangitis in a nivolumab-treated, metastatic melanoma patient in complete remission. Positron-emission tomography with computed tomography scans showed diffuse fluorodeoxyglucose (FDG) uptake in the stomach preceding upper digestive tract symptoms. Hence, positron-emission tomography with computed tomography might as well be a useful tool for early diagnosis of subclinical gastric toxicity as recently shown for colitis. Furthermore, physicians must be aware and remain vigilant to antiprogramed cell death-1 protein-related digestive toxicity that may appear very late during treatment.

Download Full-text