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Journal: Nuclear medicine and biology


PURPOSE: Development of a heptamethine cyanine based tumor-targeting PET imaging probe for noninvasive detection and diagnosis of breast cancer. METHODS: Tumor-specific heptamethine-cyanine DOTA conjugate complexed with Cu-64 (PC-1001) was synthesized for breast cancer imaging. In vitro cellular uptake studies were performed in the breast cancer MCF-7 and noncancerous breast epithelial MCF-10A cell lines to establish tumor specificity. In vivo time-dependent fluorescence and PET imaging of breast tumor xenografts in mice were performed. Blood clearance, biodistribution, and tumor-specific uptake and plasma binding of PC-1001 were quantified. Tumor histology (H&E staining) and fluorescence imaging were examined. RESULTS: PC-1001 displayed similar fluorescence properties (ε=82,880cm(-1)M(-1), E(x)/E(m)=750/820nm) to the parental dye. Time-dependent cellular accumulation indicated significantly higher probe uptake (>2-fold, 30min) in MCF-7 than MCF-10A cells and the uptake was observed to be mediated by organic anion transport peptides (OATPs) system. In vivo studies revealed that PC-1001 has desirable accumulation profile in tumor tissues, with tumor versus muscle uptake of about 4.3 fold at 24h and 5.8 fold at 48h post probe injections. Blood half-life of PC-1001 was observed to be 4.3±0.2h. Microscopic fluorescence imaging of harvested tumor indicated that the uptake of PC-1001 was restricted to viable rather than necrotic tumor cells. CONCLUSIONS: A highly efficient tumor-targeting PET/fluorescence imaging probe PC-1001 is synthesized and validated in vitro in MCF-7 breast cancer cells and in vivo in mice breast cancer xenograft model.

Concepts: Cancer, Breast cancer, Oncology, In vivo, Benign tumor, Tumor, Neoplasm, MCF-7


To improve the synthesis and quality control of carbon-11 labeled radiopharmaceuticals, we report the fully automated loop syntheses of [(11)C]raclopride and [(11)C]DASB using ethanol as the only organic solvent for synthesis module cleaning, carbon-11 methylation, HPLC purification, and reformulation.

Concepts: Oxygen, Ethanol, Solvent, Ethanol fuel


INTRODUCTION: Click chemistry, particularly the Huisgen 1,3-dipolar cycloaddition of an alkyne with an azide, has quickly become popular for site-specific radiolabeling. Recently, strain-promoted click chemistries have been developed, eliminating the need for potentially toxic copper catalysts. This study presents radiolabeling of an α(v)β(6) integrin targeting peptide (A20FMDV2) via strain-promoted click using a fluorine-18 prosthetic group, and in vitro and in vivo evaluation. METHODS: The radiotracer was prepared from and N(3)-PEG(7)-A20FMDV2 (ethanol; 10min; 35-45°C). HPLC-purified and formulated radiotracer 1 was evaluated in vitro by cell binding (DX3puroβ6, α(v)β(6)-positive; and DX3puro, α(v)β(6)-negative control) and serum stability, and in vivo using PET/CT imaging and biodistribution studies in mice. RESULTS: The radiotracer 1 was readily prepared and purified (from 2: 40±4min including HPLC, 11.9±3.2% decay corrected isolated radiochemical yield, >99% radiochemical purity, n=4) and displayed good stability (1h: >99%, saline; 94.6%, serum). Strong α(v)β(6)-targeted binding was observed in vitro (DX3puroβ6 cells, 15min: 43.2% binding, >6:1 for DX3puroβ6:DX3puro). In the mouse model DX3puroβ6-tumor binding was low (1h: 0.47±0.28% ID/g, 4h: 0.14±0.09% ID/g) and clearing from the bloodstream was via the renal and hepatobiliary routes (urine: 167±84% ID/g at 1h, 10.3±4.8% ID/g at 4h; gall bladder: 95±33% ID/g at 1h, 63±11% ID/g at 4h). CONCLUSION: Copper-free, strain-promoted click chemistry is an attractive, straightforward approach to radiolabeling. Although the [(18)F]FBA-C(6)-ADBIO-based prosthetic group did not interfere with α(v)β(6)-targeted binding in vitro, it did influence the pharmacokinetics, possibly due to its size and lipophilic nature.

Concepts: Chemistry, In vivo, In vitro fertilisation, In vitro, Organic chemistry, Mouse, Click chemistry, Azide alkyne Huisgen cycloaddition


In considering the challenges of approaches to clinical imaging, we are faced with choices that sometimes are impacted by rather dogmatic notions about what is a better or worse technology to achieve the most useful diagnostic image for the patient. For example, is PET or SPECT most useful in imaging any particular disease dissemination? The dictatorial approach would be to choose PET, all other matters being equal. But is such a totalitarian attitude toward imaging selection still valid? In the face of new receptor targeted SPECT agents one must consider the remarkable specificity and sensitivity of these agents. (99m)Tc-Tilmanocept is one of the newest of these agents, now approved for guiding sentinel node biopsy (SLNB) in several solid tumors. Tilmanocept has a Kd of 3×10(-11)M, and it specificity for the CD206 receptor is unlike any other agent to date. This coupled with a number of facts, that specific disease-associated macrophages express this receptor (100 to 150 thousand receptors), that the receptor has multiple binding sites for tilmanocept (>2 sites per receptor) and that these receptors are recycled every 15min to bind more tilmanocept (acting as intracellular “drug compilers” of tilmanocept into non-degraded vesicles), gives serious pause as to how we select our approaches to diagnostic imaging. Clinically, the size of SLNs varies greatly, some, anatomically, below the machine resolution of SPECT. Yet, with tilmanocept targeting, the SLNs are highly visible with macrophages stably accruing adequate (99m)Tc-tilmanocept counting statistics, as high target-to-background ratios can compensate for spatial resolution blurring. Importantly, it may be targeted imaging agents per se, again such as tilmanocept, which may significantly shrink any perceived chasm between the imaging technologies and anchor the diagnostic considerations in the targeting and specificity of the agent rather than any lingering dogma about the hardware as the basis for imaging approaches. Beyond the elements of imaging applications of these agents is their evolution to therapeutic agents as well, and even in the neo-logical realm of theranostics. Characteristics of agents such as tilmanocept that exploit the natural history of diseases with remarkably high specificity are the expectations for the future of patient- and disease-centered diagnosis and therapy.

Concepts: Protein, Medicine, Oncology, Medical imaging, Sensitivity and specificity, Positron emission tomography, Sentinel lymph node, Image processing


The goal of this study was to prepare a synthetic peptide derived from breast tumor associated antigen and to evaluate its potential as a breast cancer imaging agent.

Concepts: Protein, Cancer, Breast cancer, Metastasis, Chemotherapy, Pleural effusion, HER2/neu, Janet Lane-Claypon


Trithiol chelates are suitable for labeling radioarsenic (72As: 2.49 MeV β+, 26 h;77As: 0.683 MeV β-, 38.8 h) to form potential theranostic radiopharmaceuticals for PET imaging and therapy. To investigate the in vivo stability of trithiol chelates complexed with no carrier added (nca) radioarsenic, a bifunctional trithiol chelate was developed, and conjugated to bombesin(7-14)NH2as a model peptide.

Concepts: Positron emission tomography, In vivo, Ligand, Coordination chemistry, Chelation


We recently developed a chelating platform based on the macrocycle 1,4,7-triazacyclononane with up to three five-membered azaheterocyclic arms for complexation of the PET nuclides gallium-68 and copper-64. The main objective of this study was to evaluate the stability and pharmacokinetics of68Ga- and64Cu-complexes of the bifunctional chelator NODIA-Me 1 covalently bound to a PSMA targeting vector in vivo.

Concepts: In vivo, Ligand, Coordination chemistry, In vitro


Zirconium-89 (89Zr, t1/2=78.4h) liquid target (LT) production offers an approach to introduce this positron-emitting isotope to cyclotron centres without the need for a separate solid target (ST) production set up. We compared the production, purification, and antibody radiolabeling yields of89Zr-(LT) and89Zr-(ST), and assessed the feasibility of89Zr-(LT) for preclinical PET/CT.

Concepts: Atom, In vivo, Liquid, Isotope


Due to the high candidate exclusion rate during a drug development process, an early prediction of the pharmacokinetic behavior would be needed. Accordingly, high performance bioaffinity chromatography (HPBAC) approaches are growing in popularity, however, there is a lack of knowledge and no consensus about the relation between HPBAC measurements, in vivo distribution and blood brain barrier (BBB) penetration behavior. With respect to radiotracers, there is almost no reference data available for plasma protein binding (PPB), permeability (Pm) and the membrane coefficient (KIAM). Thus, this study was aimed at exploring the relevance of measuring PPB, Pm and KIAMfor the prediction of BBB penetration.

Concepts: Protein, Pharmacology, Brain, Blood, Measurement, In vivo, Test method, Pharmacokinetics


Thermal neutron activation of152Sm [152Sm(n,γ)153Sm] using natural or isotopically enriched (by152Sm) samarium target is the established route for production of153Sm used for preparation of153Sm-EDTMP for pain palliation in cancer patients with disseminated bone metastases. However, some long-lived radionuclidic contaminants of Eu, such as,154Eu (t½=8.6y) are also produced during the target activation process. This leads to detectable amount of Eu radionuclidic contaminants in patients' skeleton even years after administration with therapeutic doses of153Sm-EDTMP. Further, the presence of such contaminants in153Sm raises concerns related to radioactive waste management. The aim of the present study was to develop and demonstrate a viable method for large-scale purification of153Sm from radionuclidic contaminants of Eu.

Concepts: Cancer, Oncology, Neutron, Nuclear fission, Waste, Radioactive waste, Deep geological repository, Lake Karachay