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Repeatability of brown adipose tissue activation measured by [18F]FDG PET after beta3-adrenergic stimuli in a mouse model.

Male C57BL/6 mice underwent [18F]FDG-PET at baseline without stimulation (T0-NS), on three consecutive days after intravenous administration of the selective β3-adrenergic agonist CL316243 (T1-CL, T2-CL, T3-CL), and without stimuli after 1 and 2weeks (T7-NS and T14-NS). The standardized uptake value (SUVmax), BAT metabolic volume (BMV), and total BAT glycolysis (TBG) were measured in each scanning session, with statistical groupwise comparisons by ANOVA and post hoc Tukey test. SUVmax, BMV, and TBG values showed no significant differences between the three PET scans without stimuli, but were significantly higher after CL316243 administration (p<0.0001). The mean coefficient of variation (CoV) of PET within individuals was 49% at baseline but only 9% with pharmacological stimulation. The study demonstrated that administration of the selective β3-adrenergic receptor agonist CL316243 (CL) in mice leads to consistent metabolic activation of brown adipose tissue (BAT), as measured by [18F]FDG-PET. We also demonstrated metabolic activation by repeated pharmacological challenge, without evidence of hysteresis. Thus, the methods used in the current work should serve for further studies on BAT metabolism in experimental animals, with translational value for clinical research.

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Production, isolation, and shipment of clinically relevant quantities of astatine-211: A simple and efficient approach to increasing supply.

Our method allows shipment of 211At in various quantities in a form convenient for further radiochemistry. For this study, a 3-octanone impregnated Amberchrom CG300M resin bed in a column cartridge was used to separate 211At from the bismuth matrix on site at the production accelerator (Texas A&M) in preparation for shipping. Aliquots of 6M HNO3 containing up to ≈2.22GBq of 211At from the dissolved target were successfully loaded and retained on columns. Exempt packages (<370MBq) were shipped to a destination radiochemistry facility, University of Texas MD Anderson Cancer Center, in the form of a convenient air-dried column. Type A packages have been shipped overnight to University of Alabama at Birmingham. Air-dried column hold times of various lengths did not inhibit simple and efficient recovery of 211At. Solution eluted from the column was sufficiently high in specific activity to successfully radiolabel a model compound, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1), with 211At. The method to prepare and ship 211At described in this manuscript has also been used to ship larger quantities of 211At a greater distance to University of Alabama at Birmingham. The successful proof of this method paves the way for the distribution of 211At from Texas A&M University to research institutions and clinical oncology centers in Texas and elsewhere. Use of this simple method at other facilities has the potential increase the overall availability of 211At for preclinical and clinical studies.

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Preparation and evaluation of 111In-labeled liposomes containing phosphatidylglycerol for detection of macrophages in atherosclerotic plaques.

Macrophage infiltration is a characteristic feature of atherosclerotic plaque progression. Since liposomes containing 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) are efficiently phagocytosed by macrophages, we deduced that radiolabeled liposomes containing DSPG could potentially be used for nuclear imaging of vulnerable atherosclerotic plaques. Indium-111 (111In)-labeled liposomes containing different ratios of DSPG were developed with a high labeling efficiency. 111In-labeled liposomes with higher DSPG content showed higher uptake by macrophage-like RAW264 cells. A biodistribution study demonstrated rapid blood clearance and selective accumulation in the liver and spleen, especially in normal mice injected with 111In-labeled liposomes with higher DSPG content. Accumulation in atherosclerotic plaques was evaluated using 111In-labeled DSPG liposomes, which had the highest DSPG content among the studied liposomes. 111In-labeled DSPG liposomes accumulated in the plaques and the radioactive regions were mostly consistent with the distribution of macrophages. The target-to-non-target ratio of 111In-labeled DSPG liposomes was higher than that of 111In-labeled control liposomes without DSPG. These results suggest that 111In-labeled liposomes containing DSPG are useful for nuclear medical diagnosis of atherosclerotic plaques.

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Imaging of cell death in malignancy: Targeting pathways or phenotypes?

Cell death is fundamental in health and disease and resisting cell death is a hallmark of cancer. Treatment of malignancy aims to cause cancer cell death, however current clinical imaging of treatment response does not specifically image cancer cell death but assesses this indirectly either by changes in tumor size (using x-ray computed tomography) or metabolic activity (using 2-[18F]fluoro-2-deoxy-glucose positron emission tomography). The ability to directly image tumor cell death soon after commencement of therapy would enable personalised response adapted approaches to cancer treatment that is presently not possible with current imaging, which is in many circumstances neither sufficiently accurate nor timely. Several cell death pathways have now been identified and characterised that present multiple potential targets for imaging cell death including externalisation of phosphatidylserine and phosphatidylethanolamine, caspase activation and La autoantigen redistribution. However, targeting one specific cell death pathway carries the risk of not detecting cell death by other pathways and it is now understood that cancer treatment induces cell death by different and sometimes multiple pathways. An alternative approach is targeting the cell death phenotype that is "agnostic" of the death pathway. Cell death phenotypes that have been targeted for cell death imaging include loss of plasma membrane integrity and dissipation of the mitochondrial membrane potential. Targeting the cell death phenotype may have the advantage of being a more sensitive and generalisable approach to cancer cell death imaging. This review describes and summarises the approaches and radiopharmaceuticals investigated for imaging cell death by targeting cell death pathways or cell death phenotype.

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Integrin αvβ3 and EGFR dual-targeted [64Cu]Cu-NOTA-RGD-GE11 heterodimer for PET imaging in pancreatic cancer mouse model.

Radiolabeled heterodimeric peptide has emerged as a highly promising targeting strategy for PET imaging due to their superior properties. RGD and GE11 are two peptides binding to receptor integrin αvβ3 and EGFR, respectively, which both overexpress in many different types of tumors. This study focuses on the synthesis and evaluation of a RGD and GE11-containing heterodimeric radiotracer [64Cu]Cu-NOTA-RGD-GE11 for PET imaging of tumors that simultaneously overexpress integrin αvβ3 and EGFR. [64Cu]Cu-NOTA-RGD-GE11 was prepared by the conjugation of RGD-PEG4-NOTA-N3 and GE11-PEG4-BCN via metal-free click chemistry, followed by radiolabeling with 64Cu. Cell uptake and efflux studies, saturation binding assay, the animal PET/CT and biodistribution studies were conducted to characterize the biological properties of [64Cu]Cu-NOTA-RGD-GE11. [64Cu]Cu-NOTA-RGD-GE11 was synthesized with a radiochemical purity of >97% and molar activity of 23GBq/μmol at the end of synthesis. [64Cu]Cu-NOTA-RGD-GE11 showed moderate hydrophilicity, good stability in mouse serum and high specific uptake by the human pancreatic cancer cell line (BxPC3) in the in vitro studies. Compared to the two monomeric counterparts [64Cu]Cu-NOTA-RGD and [64Cu]Cu-NOTA-GE11, [64Cu]Cu-NOTA-RGD-GE11 demonstrated significantly improved tumor uptakes (e.g. 4.63±0.25 %ID/g vs 1.24±0.18 %ID/g and 0.77±0.13 %ID/g, 2h after injection, p<0.05) in the subsequent in vivo evaluation in mice bearing BxPC3 xenograft. Tumor uptake could be blocked in the presence of both non-radioactive c(RGDyK) and GE11 peptides, indicating good tumor specificity of [64Cu]Cu-NOTA-RGD-GE11 in vivo. The results suggested that the as-developed [64Cu]Cu-NOTA-RGD-GE11 could serve as a potential PET tracer for the noninvasive imaging of integrin αvβ3 and EGFR expression in tumors.

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Evaluation of affinity matured Affibody molecules for imaging of the immune checkpoint protein B7-H3.

B7-H3 (CD276), an immune checkpoint protein, is a promising molecular target for immune therapy of malignant tumours. Sufficient B7-H3 expression level is a precondition for successful therapy. Radionuclide molecular imaging is a powerful technique for visualization of expression levels of molecular targets in vivo. Use of small radiolabelled targeting proteins would enable high-contrast radionuclide imaging of molecular targets if adequate binding affinity and specificity of an imaging probe could be provided. Affibody molecules, small engineered affinity proteins based on a non-immunoglobulin scaffold, have demonstrated an appreciable potential in radionuclide imaging. Proof-of principle of radionuclide visualization of expression levels of B7-H3 in vivo was demonstrated using the [99mTc]Tc-AC12-GGGC Affibody molecule. We performed an affinity maturation of AC12, enabling selection of clones with higher affinity. Three most promising clones were expressed with a -GGGC (triglycine-cysteine) chelating sequence at the C-terminus and labelled with technetium-99m (99mTc). 99mTc-labelled conjugates bound to B7-H3-expressing cells specifically in vitro and in vivo. Biodistribution in mice bearing B7-H3-expressing SKOV-3 xenografts demonstrated improved imaging properties of the new conjugates compared with the parental variant [99mTc]Tc-AC12-GGGC. [99mTc]Tc-SYNT-179 provided the strongest improvement of tumour-to-organ ratios. Thus, affinity maturation of B7-H3 Affibody molecules could improve biodistribution and targeting properties for imaging of B7-H3-expressing tumours.

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Automated production of [68Ga]Ga-DOTA-exendin-4 via fractionated radionuclide generator elution on a cassette based synthesis module.

PET/CT imaging of glucagon-like peptide receptor 1has recently filled a gap in reliably diagnosing insulinoma through non-invasive means. 68Ga-labelled derivatives of exendin-4 show high sensitivity as well as sufficient serum stability to enable routine clinical application. Here, we provide data for automated production of [68Ga][Nle14,Lys40(Ahx-DOTA-Ga)NH2]exendin-4 ([68Ga]Ga-DOTA-exendin-4) on a cassette based synthesis module (Modular-Lab PharmTracer, Eckert & Ziegler) using commercially available cassettes in combination with an approved 68Ge/68Ga generator (GalliaPharm, Eckert & Ziegler). This setup ensured high reproducibility as well as low radiation burden for the production team. Quality control including determination of radiochemical purity was performed by RP-HPLC using a water/0.1% TFA/acetonitrile gradient on a C18 column. A modified TLC system with ammonium acetate & methanol as mobile phase and a novel limit test for determination of polysorbate 80 content in the final formulation are also described in this study. Reliable yields as well as high molar activity for patient use were only achieved using a fractionated elution approach. Batch data showed radiochemical purity of >93% as determined by RP-HPLC and TLC as well as good stability over 2h post production. Testing for polysorbate 80 confirmed a concentration<1mg/mL in the final product solution. Specifications for routine production were established based on existing Pharmacopeia monographs for other radiopharmaceuticals and were validated with 5 master batches. The described synthesis method enables reproducible, automated in-house production of [68Ga]Ga-DOTA-exendin-4 for routine clinical application.

Open Access
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