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Abstract: Production of 38Cl and 34mCl via the (d, α) reaction on natural argon and 36Ar reveal medical cyclotrons’ ability to supply these isotopes in small quantities. 38Cl provides an inexpensive developmental tool, while 34mCl is a positron emitter of interest in PET imaging. Production yields, cyclotron target development, cryo-recovery of enriched gases, and nucleophilic chemistry of a model compound are described. [Copyright &y& Elsevier]

Functional neurochemical imaging can indicate neurotransmitter release by detecting changes in receptor occupancy. A dual tracer positron emission tomography (PET) technique is presented here to extend such studies by simultaneously measuring changes in regional cerebral blood flow (rCBF). This would permit correlations of task or drug induced changes in rCBF and neurochemical function. In this proposed method, the rapidly varying signal from a blood flow tracer is distinguished from the slowly changing signal due to a long-lived neurochemical tracer. As a proof of principle, baseline studies were carried out in rhesus monkeys. Two monkeys were anesthetized with isoflurane, and [18F]fallypride (t1/2=110 min), a dopamine D2 receptor antagonist, was injected. Starting 99–137 min after injection, PET images were acquired every 10 s while the blood flow tracer [17F]fluoromethane (t1/2=65 s) was administered by inhalation in a repeating pattern of 45 s on/45 s off. The observed time–activity curves for 2 ml brain regions were fit with a three compartment lung–body–brain model of fluoromethane kinetics with whole brain perfusion fixed. Comparing consecutive 6 min scans, reproducibility of relative rCBF and striatal [18F]fallypride concentration were 9 and 8%, respectively. [Copyright &y& Elsevier]

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide 45Ti for radiopharmaceutical applications. Herein, we evaluate the Ti(IV)‐coordination chemistry of four catechol‐based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN‐CAM readily form mononuclear Ti(IV) species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN‐CAM form mononuclear complexes with the short‐lived, positron‐emitting radionuclide 45Ti(IV), and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the 45Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent‐DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [45Ti][Ti(Ent‐DUPA)]2− complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %, n=5), and low off‐target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with 45Ti(IV), provides a foundation for advancing the application of 45Ti in nuclear medicine, and reveals that Ent can be repurposed as a 45Ti‐complexing cargo for targeted nuclear imaging applications. [ABSTRACT FROM AUTHOR]

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide 45Ti for radiopharmaceutical applications. Herein, we evaluate the Ti(IV)‐coordination chemistry of four catechol‐based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN‐CAM readily form mononuclear Ti(IV) species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN‐CAM form mononuclear complexes with the short‐lived, positron‐emitting radionuclide 45Ti(IV), and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the 45Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent‐DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [45Ti][Ti(Ent‐DUPA)]2− complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %, n=5), and low off‐target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with 45Ti(IV), provides a foundation for advancing the application of 45Ti in nuclear medicine, and reveals that Ent can be repurposed as a 45Ti‐complexing cargo for targeted nuclear imaging applications. [ABSTRACT FROM AUTHOR]

Purpose: We dual-labeled an intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody (mAb) and evaluated its effectiveness for lesion detection and surgical navigation in pancreatic ductal adenocarcinoma (PDAC) via multiple noninvasive imaging approaches, including positron emission tomography (PET), near-infrared fluorescence (NIRF), and Cerenkov luminescence imaging (CLI). Methods: ICAM-1 expression in PDAC cell lines (BxPC-3 and AsPC-1) was assessed via flow cytometry and immunofluorescent staining. An ICAM-1 mAb labeled by IRDye 800CW and radionuclide zirconium-89 (denoted as [89Zr]Zr-DFO-ICAM-1-IR800) was synthesized. Its performance was validated via in vivo comparative PET/NIRF/CLI and biodistribution (Bio-D) studies in nude mice bearing subcutaneous BxPC-3/AsPC-1 tumors or orthotopic BxPC-3 tumor models using nonspecific IgG as an isotype control tracer. Results: ICAM-1 expression was strong in the BxPC-3 and minimal in the AsPC-1 cell line. Both multimodality imaging and Bio-D data exhibited more prominent uptake of [89Zr]Zr-DFO-ICAM-1-IR800 in BxPC-3 tumors than in AsPC-1 tumors. The uptake of [89Zr]Zr-DFO-IgG-IR800 in BxPC-3 tumors was similar to that of [89Zr]Zr-DFO-ICAM-1-IR800 in AsPC-1 tumors. These results demonstrate the desirable affinity and specificity of [89Zr]Zr-DFO-ICAM-1-IR800 compared to [89Zr]Zr-DFO-IgG-IR800. Orthotopic BxPC-3 tumor foci could also be clearly delineated by [89Zr]Zr-DFO-ICAM-1-IR800. An intermodal match was achieved in the ICAM-1–targeted immunoPET/NIRF/CLI. The positive expression levels of ICAM-1 in BxPC-3 tumor tissue were further confirmed by immunohistopathology. Conclusion: We successfully developed a dual-labeled ICAM-1–targeted tracer for PET/NIRF/CLI of PDAC that can facilitate better diagnosis and intervention of PDAC upon clinical translation. [ABSTRACT FROM AUTHOR]

The radioisotopes of bromine are uniquely suitable radiolabels for small molecule theranostic radiopharmaceuticals but are of limited availability due to production challenges. Significantly improved methods were developed for the production and radiochemical isolation of clinical quality 76Br, 77Br, and 80mBr. The radiochemical quality of the radiobromine produced using these methods was tested through the synthesis of a novel 77Br-labeled inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1), a DNA damage response protein. 76Br, 77Br, and 80mBr were produced in high radionuclidic purity via the proton irradiation of novel isotopically-enriched Co76Se, Co77Se, and Co80Se intermetallic targets, respectively. Radiobromine was isolated through thermal chromatographic distillation in a vertical furnace assembly. The 77Br-labeled PARP inhibitor was synthesized via copper-mediated aryl boronic ester radiobromination. Cyclotron production yields were 103 ± 10 MBq∙μA−1∙h−1 for 76Br, 88 ± 10 MBq∙μA−1∙h−1 for 80mBr at 16 MeV and 17 ± 1 MBq∙μA−1∙h−1 for 77Br at 13 MeV. Radiobromide isolation yields were 76 ± 11% in a small volume of aqueous solution. The synthesized 77Br-labeled PARP-1 inhibitor had a measured apparent molar activity up to 700 GBq/μmol at end of synthesis. A novel selenium alloy target enabled clinical-scale production of 76Br, 77Br, and 80mBr with high apparent molar activities, which was used to for the production of a new 77Br-labeled inhibitor of PARP-1. New methods for the cyclotron production and isolation of radiobromine improved the production capacity of 77Br by a factor of three and 76Br by a factor of six compared with previous methods. Preclinical translational research of 77Br-based Auger electron radiotherapeutics, such as those targeting PARP-1, will require the production of GBq-scale 77Br, which necessitates next-generation, high-yielding, isotopically-enriched cyclotron targets, such as the novel intermetallic Co77Se. [ABSTRACT FROM AUTHOR]

52gMn is a promising radionuclide for positron emission tomography (PET). Enriched 52Cr targets are required to minimize formation of 54Mn radioisotopic impurities during production with proton beams. The need for radioisotopically pure 52gMn, accessibility and cost of 52Cr, sustainability of the radiochemical process, and potential for iterative purification of target materials motivate this development of recyclable, electroplated 52Cr metal targets and radiochemical isolation and labeling with resulting >99.89% radionuclidically pure 52gMn. The run-to-run replating efficiency is 60 ± 20%, and unplated chromium from this method is recovered with 94% efficiency as 52CrCl 3 hexahydrate. The decay-corrected molar activity of chemically isolated 52gMn for common chelating ligands was 376 MBq/μmol. • Manganese-52g is a promising radionuclide for positron emission tomography. • Enriched 52Cr targets are required to minimize formation of 54Mn radioisotopic impurities during production with proton beams. • Development of recyclable, electroplated 52Cr metal targets. [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of photodynamic therapy is limited by the ability of light to penetrate tissues. Due to this limitation, Cerenkov luminescence (CL) from radionuclides has recently been proposed as an alternative light source in a strategy referred to as Cerenkov radiation‐induced therapy (CRIT). Semiconducting polymer nanoparticles (SPNs) have ideal optical properties, such as large absorption cross‐sections and broad absorbance, which can be utilized to harness the relatively weak CL produced by radionuclides. SPNs can be doped with photosensitizers and have ≈100% energy transfer efficiency by multiple energy transfer mechanisms. Herein, an optimized photosensitizer‐doped SPN is investigated as a nanosystem to harness and amplify CL for cancer theranostics. It is found that semiconducting polymers significantly amplify CL energy transfer efficiency. Bimodal positron emission tomography (PET) and optical imaging studies show high tumor uptake and retention of the optimized SPNs when administered intravenously or intratumorally. Lastly, it is found that photosensitizer‐doped SPNs have excellent potential as a cancer theranostics nanosystem in an in vivo tumor therapy study. This study shows that SPNs are ideally suited to harness and amplify CL for cancer theranostics, which may provide a significant advancement for CRIT that are unabated by tissue penetration limits. [ABSTRACT FROM AUTHOR]

Recent advances in molecular characterization of tumors have made possible the emergence of new types of cancer therapies where traditional cytotoxic drugs and nonspecific chemotherapy can be complemented with targeted molecular therapies. One of the main revolutionary treatments is the use of monoclonal antibodies (mAbs) that selectively target the disseminated tumor cells while sparing normal tissues. mAbs and related therapeutics can be efficiently radiolabeled with a wide range of radionuclides to facilitate preclinical and clinical studies. Non‐invasive molecular imaging techniques, such as Positron Emission Tomography (PET), using radiolabeled mAbs provide useful information on the whole‐body distribution of the biomolecules, which may enable patient stratification, diagnosis, selection of targeted therapies, evaluation of treatment response, and prediction of dose limiting tissue and adverse effects. In addition, when mAbs are labeled with therapeutic radionuclides, the combination of immunological and radiobiological cytotoxicity may result in enhanced treatment efficacy. The pharmacokinetic profile of antibodies demands the use of long half‐life isotopes for longitudinal scrutiny of mAb biodistribution and precludes the use of well‐stablished short half‐life isotopes. Herein, we review the most promising PET radiometals with chemical and physical characteristics that make the appealing for mAb labeling, highlighting those with theranostic radioisotopes. [ABSTRACT FROM AUTHOR]

Fe, Cu, and Al stacked foils were irradiated by 90 MeV protons at the Los Alamos Neutron Science Center’s Isotope Production Facility to measure nuclear cross sections for the production of medically relevant isotopes, such as 52g Mn, 54 Mn, 48 Cr, 55 Co, 58m Co and 57 Ni. The decay of radioactive isotopes produced during irradiation was monitored using high-purity germanium gamma spectroscopy over the months following irradiation. Proton fluence was determined using the nat Al(p,x) 22 Na, nat Cu(p,x) 62 Zn nat Cu(p,x) 65 Zn, and nat Cu(p,x) 56 Co monitor reactions. Calculated cross sections were compared against literature values and theoretical TALYS predictions. Notably this work includes the first reported independent cross section measurements of nat Cu(p,x) 58m Co and nat Cu(p,x) 58g Co. [ABSTRACT FROM AUTHOR]

The neuropeptide oxytocin is part of a neuroendocrine system that has physiological effects ranging from ensuring uterine myometrial contractions at parturition and post-partum mammary gland milk ejection to the modulation of neural control of social relationships. This initial study was performed to investigate the potential use of positron emission tomography (PET) for localizing oxytocin receptors in two New World primates. Three biomarkers for PET ( 1 – 3 ) that are known to have high affinity and selectivity for the human oxytocin receptor were investigated in the common marmoset ( Callithrix jacchus ) via PET imaging. Brain penetration, and uptake in the salivary gland area were both observed with biomarkers 2 and 3 . No brain penetration was observed with 1 , but uptake was observed more specifically in several peripheral endocrine glands compared to 2 or 3 . Biomarker 2 , which displayed the best brain penetration of the three biomarkers in the marmoset, was then investigated in the monogamous coppery titi monkey ( Callicebus cupreus ) in a brain scan and a limited full body scan. No significant brain penetration of 2 was observed in the titi monkey, but significant uptake was observed in various locations throughout the periphery. Metabolism of 2 was suspected to have been significant based upon HPLC analysis of blood draws, but parent compound was still present near the end of the scan. Follow-up investigations will focus on next generation biomarkers bearing improved binding characteristics and brain penetrability as well as investigating tissue in regions where biomarker uptake was observed. [ABSTRACT FROM AUTHOR]

Purpose: Without a standard test for pancreatic carcinomas, this highly lethal disease is normally diagnosed at its advanced stage, leading to a low survival rate of patients. Trophoblast cell-surface antigen 2 (Trop-2), a transmembrane glycoprotein, is associated with cell proliferation and highly expressed in most of solid epithelial tumors, including pancreatic cancer. A non-invasive method of imaging Trop-2 would greatly benefit clinical diagnosis and monitoring of pancreatic cancer. In the current study, 89Zr-labeled anti-Trop-2 antibody (AF650) was recruited for the systemic evaluation of Trop-2 as an immunoPET target for pancreatic cancer imaging. Methods: AF650 was conjugated with desferrioxamine (DFO) and then radiolabeled with 89Zr. Trop-2 expression levels were determined in three pancreatic cancer cell lines (BxPC-3, MIA PaCa-2, and AsPC-1) via western blot, flow cytometry, saturation binding assay, and immunofluorescence staining. The targeting capacity of 89Zr-DFO-AF650 was evaluated in mouse models with subcutaneous xenograft of pancreatic cancers via PET imaging and bio-distribution studies. In addition, a Trop-2-positive orthotopic cancer model was recruited for further validating the targeting specificity of 89Zr-DFO-AF650. Results: BxPC-3 cells expressed high levels of Trop-2, while AsPC-1 and MIA PaCa-2 cells expressed low levels of Trop-2. Additionally, 89Zr-DFO-AF650 exhibited high specificity to Trop-2 in BxPC-3 cells (Kd = 22.34 ± 2.509 nM). In subcutaneous xenograft models, about 28.8 ± 7.63%ID/g tracer accumulated in the BxPC-3 tumors at 120 h post injection, which was much higher than those reaching MIA PaCa-2 (6.76 ± 2.08%ID/g) and AsPC-1 (3.51 ± 0.69%ID/g) tumors (n = 4). More importantly, 89Zr-DFO-AF650 could efficiently distinguish primary tumors in the orthotopic BxPC-3 cancer model, showing high correlation between PET imaging and bio-distribution and sensitivity. Conclusions: 89Zr-DFO-AF650 can be effectively used to detect pancreatic cancer via Trop-2-mediated immunoPET in vivo, clearly revealing the great potential of Trop-2-based non-invasive imaging in pancreatic cancer detection and treatment monitoring. [ABSTRACT FROM AUTHOR]

Any tracer in fetal tissue comes from maternal arterial blood. Provided steady state is achieved and intermediate compartments are reversible, the Logan graphical methods should be applicable to the assessment of binding parameters in the fetal brain. Two pregnant rhesus macaques were studied with fallypride and the Logan method was used to assess dopamine receptor distribution volume ratios (DVRs) in both maternal and fetal striatum. The agreement between fetal striatal DVRs using maternal arterial blood and maternal and fetal cerebellum as input functions strongly supports our hypothesis that the conditions necessary for graphical analysis have been met. [ABSTRACT FROM AUTHOR]

We used transcranial magnetic stimulation (TMS) in combination with positron emission tomography (PET) to investigate the effective connectivity of four cortical regions within the same study. By employing [17F]-[CH3F] ([17F]-fluoromethane) as a radiotracer of blood-flow, we were able to obtain increased sensitivity compared to [15O]-H2O for both cortical and subcortical structures. The brain areas investigated were left primary motor cortex, right primary visual cortex, and left and right prefrontal areas. We found that each site of stimulation yielded a different pattern of activation/deactivation consistent with its anatomical connectivity. Moreover, we found that TMS of prefrontal and motor cortical areas gave rise to trans-synaptic activation of subcortical circuits. [Copyright &y& Elsevier]

Lymphoma is a heterogeneous disease with varying clinical manifestations and outcomes. Many subtypes of lymphoma, such as Burkitt′s lymphoma and diffuse large B cell lymphoma, are highly aggressive with dismal prognosis even after conventional chemotherapy and radiotherapy. As such, exploring specific biomarkers for lymphoma is of high clinical significance. Herein, a potential marker, CD38, is investigated for differentiating lymphoma. A CD38‐targeting monoclonal antibody (mAb, daratumumab) is then radiolabeled with Zr‐89 and Lu‐177 for theranostic applications. As the diagnostic component, the Zr‐89‐labeled mAb is highly specific in delineating CD38‐positive lymphoma via positron emission tomography (PET) imaging, while the Lu‐177‐labeled mAb serves well as the therapeutic component to suppress tumor growth after a one‐time administration. These results strongly suggest that CD38 is a lymphoma‐specific marker and prove that 89Zr/177Lu‐labeled daratumumab facilitates immunoPET imaging and radioimmunotherapy of lymphoma in preclinical models. Further clinical evaluation and translation of this CD38‐targeted theranostics may be of significant help in lymphoma patient stratification and management. [ABSTRACT FROM AUTHOR]

We report an extraction chromatography-based method via Actinide Resin for the isolation of radio-manganese from both natural chromium and isotopically enriched iron targets for cyclotron production of 52gMn and 51Mn. For the separation of 52gMn from natCr, a decay-corrected radiochemical yield of 83.7 ± 8.4% was achieved. For 51Mn from 54Fe, a decay-corrected radiochemical yield of 78 ± 11% was achieved. This automatable method efficiently isolates both radionuclides from accelerator target material. [ABSTRACT FROM AUTHOR]

Lymphoma is a heterogeneous disease with varying clinical manifestations and outcomes. Many subtypes of lymphoma, such as Burkitt′s lymphoma and diffuse large B cell lymphoma, are highly aggressive with dismal prognosis even after conventional chemotherapy and radiotherapy. As such, exploring specific biomarkers for lymphoma is of high clinical significance. Herein, a potential marker, CD38, is investigated for differentiating lymphoma. A CD38‐targeting monoclonal antibody (mAb, daratumumab) is then radiolabeled with Zr‐89 and Lu‐177 for theranostic applications. As the diagnostic component, the Zr‐89‐labeled mAb is highly specific in delineating CD38‐positive lymphoma via positron emission tomography (PET) imaging, while the Lu‐177‐labeled mAb serves well as the therapeutic component to suppress tumor growth after a one‐time administration. These results strongly suggest that CD38 is a lymphoma‐specific marker and prove that 89Zr/177Lu‐labeled daratumumab facilitates immunoPET imaging and radioimmunotherapy of lymphoma in preclinical models. Further clinical evaluation and translation of this CD38‐targeted theranostics may be of significant help in lymphoma patient stratification and management. [ABSTRACT FROM AUTHOR]

• A non-destructive target durability test was performed on an isotope harvesting target with proton irradiation. • Radionuclides produced in the target shell acted as radiotracers to measure target degradation. • Estimates were made for isotope harvesting target lifetimes based on the measured target corrosion rate. • Radiolysis products were measured at much lower levels than are predicted with literature primary production yields. • The level of H 2 O 2 measured was found to correlate with beam intensity. A high intensity proton irradiation was performed with the flowing-water isotope harvesting target at the University of Wisconsin-Madison Cyclotron Laboratory to measure the rate of degradation of the target shell during irradiation conditions. The beam reached an intensity of 34 µA by the end of the irradiation and covered an area of 0.7 cm2 on the target. Radiolysis products, such as H 2 O 2 , H 2 , and O 2 , were measured in the bulk water of the system and found to be present at much lower levels than predicted by literature escape yields. Radionuclides formed in the target shell were measured in the system water as a radiotracer for target degradation. Using a simple, beam intensity dependent model, a corrosion rate of 1.5E-6 μm/(μA*s) was found to match the measured radiotracer activities at various points in the irradiation. This rate was used to extrapolate the lifetime of future isotope harvesting targets at the NSCL and FRIB, using the areal power density of different ion beams to scale the corrosion rate. [ABSTRACT FROM AUTHOR]

The manifestation of acute kidney injury (AKI) is associated with poor patient outcomes, with treatment options limited to hydration or renal replacement therapies. The onset of AKI is often associated with a surfeit of reactive oxygen species. Here, it is shown that selenium‐doped carbon quantum dots (SeCQDs) have broad‐spectrum antioxidant properties and prominent renal accumulation in both healthy and AKI mice. Due to these properties, SeCQDs treat or prevent two clinically relevant cases of AKI induced in murine models by either rhabdomyolysis or cisplatin using only 1 or 50 µg per mouse, respectively. The attenuation of AKI in both models is confirmed by blood serum measurements, kidney tissue staining, and relevant biomarkers. The therapeutic efficacy of SeCQDs exceeds amifostine, a drug approved by the Food and Drug Administration that also acts by scavenging free radicals. The findings indicate that SeCQDs show great potential as a treatment option for AKI and possibly other ROS‐related diseases. [ABSTRACT FROM AUTHOR]

Both scandium-44 and yttrium-86 are popular PET isotopes with appropriate half-lives for immuno-positron emission tomography (immuno-PET) imaging. Herein, a new bifunctional H4pypa ligand, H4pypa-phenyl-NCS, is synthesized, conjugated to a monoclonal antibody, TRC105, and labeled with both radionuclides to investigate the long-term in vivo stability of each complex. While the 44Sc-labeled radiotracer exhibited promising pharmacokinetics and stability in 4T1-xenograft mice (n = 3) even upon prolonged interactions with blood serum proteins, the progressive bone uptake of the 86Y-counterpart indicated in vivo demetallation, obviating H4pypa as a suitable chelator for Y3+ ion in vivo. The solution chemistry of [natY(pypa)]− was studied in detail and the complex found to be thermodynamically stable in solution with a pM value 22.0, ≥3 units higher than those of the analogous DOTA- and CHX-A′′-DTPA-complexes; the 86Y-result in vivo was therefore most unexpected. To explore further this in vivo lability, Density Functional Theory (DFT) calculation was performed to predict the geometry of [Y(pypa)]− and the results were compared with those for the analogous Sc- and Lu-complexes; all three adopted the same coordination geometry (i.e. distorted capped square antiprism), but the metal-ligand bonds were much longer in [Y(pypa)]− than in [Lu(pypa)]− and [Sc(pypa)]−, which could indicate that the size of the binding cavity is too small for the Y3+ ion, but suitable for both the Lu3+ and Sc3+ ions. Considered along with results from [86Y][Y(pypa-phenyl-TRC105)], it is noted that when matching chelators with radionuclides, chemical data such as the thermodynamic stability and in vitro inertness, albeit useful and necessary, do not always translate to in vivo inertness, especially with the prolonged blood circulation of the radiotracer bound to a monoclonal antibody. Although H4pypa is a nonadentate chelator, which theoretically matches the coordination number of the Y3+ ion, we show herein that its binding cavity, in fact, favors smaller metal ions such as Sc3+ and Lu3+ and further exploitation of the Sc-pypa combination is desired. [ABSTRACT FROM AUTHOR]

Intrathecal injection, drugs transporting along perivascular spaces, represents an important route for maintaining blood–brain barrier (BBB) integrity after cerebral ischemia/reperfusion (I/R) injury. However, after being directly injected into cerebrospinal fluid (CSF), the temporal and spatial changes in the distribution of therapeutic protein drugs have remained unknown. Here, with positron emission tomography (PET) imaging, the uptake of 89Zr‐agrin is noninvasively and dynamically monitored. These data demonstrate the time–activity curve of drugs in the brain subregions and their spatial distribution in different organs after intrathecal administration. Furthermore, agrin treatment effectively inhibits BBB disruption by reducing the loss of tight‐junctional proteins. Importantly, the infarct volume is reduced; the number of apoptotic neurons is decreased; and neurological function is improved in mouse I/R injury models. Thus, intrathecal injection of agrin provides the basis for a new strategy to research and develop protein drugs for reducing the aggravation of I/R injury. [ABSTRACT FROM AUTHOR]

We report the first targeted nuclear medicine application of the lanthanum radionuclides 132/135La. These isotopes represent a matched pair for diagnosis via the positron emissions of 132La and therapy mediated by the Auger electron emissions of 135La. We identify two effective chelators, known as DO3Apic and macropa, for these radionuclides. The 18‐membered macrocycle, macropa, bound 132/135La with better molar activity than DO3Apic under similar conditions. These chelators were conjugated to the prostate‐specific membrane antigen (PSMA)‐targeting agent DUPA to assess the use of radiolanthanum for in vivo imaging. The 132/135La‐labeled targeted constructs showed high uptake in tumor xenografts expressing PSMA. This study validates the use of these radioactive lanthanum isotopes for imaging applications and motivates future work to assess the therapeutic effects of the Auger electron emissions of 135La. [ABSTRACT FROM AUTHOR]

Cobalt-55 and -58m form a theranostic pair that has relevant properties for cancer research. We report a cation exchange chromatography/extraction chromatography method that separates cyclotron-produced 55/58mCo from 54/57Fe in <1.5 h, recovers >85% Co and achieves [55Co]Co-NOTA and -DOTA AMA 89 ± 48 and 35 ± 7 MBq/nmol (EOB), respectively. Cobalt-55 and -58m were quantitatively labeled to functionalized NOTA at 106 and 50 MBq/nmol (EOB), respectively, corroborating measured AMA. This method is faster than previously published methods and achieves better [55/58mCo]Co-NOTA and -DOTA AMA. • [55Co]Co-NOTA/DOTA apparent molar activity 89 ± 48/35 ± 7 MBq/nmol (N=6) at EOB. • 58mCo quantitatively labeled at 50 MBq/nmol to functionalized NOTA (EOB). • 55/58mCo separated from 54/57Fe via cation exchange and extraction chromatography in < 1.5 h. • >85% Co RCY in 1 mL and >99.99% 55Co radionuclidic purity. • >98% 54/57Fe recovery and resulting 54/57Fe can be electrodeposited. [ABSTRACT FROM AUTHOR]

Abstract We report a novel, precipitation-based method for the isolation of Mn from Cr targets for cyclotron production of 52gMn. The separation produces no-carrier-added 52gMn with a decay corrected radiochemical yield of 85 ± 3% and apparent molar activity for DOTA of 1.3 GBq/μmol. This method reduces stable metallic impurities in the purified 52gMn compared to previously reported chromatographic methods. Highlights • Radiochemical separation using a 2-phase precipitation method and single extraction chromatography column. • Separation strategy for production no-carrier-added 52gMn. • Process allows for chelation studies with DOTA. [ABSTRACT FROM AUTHOR]

Abstract We present a simplified, automatable single-column radiochemical separation method using the extraction chromatographic branched-DGA resin for the production of no-carrier-added 86Y with a radiochemical yield higher than 95%, an apparent molar activity of 1.4 ± 0.4 Ci/μmol (DOTA) and 2.3 ± 0.7 Ci/μmol (DTPA), and a run-to-run recycling efficiency of the isotopically-enriched target of 98 ± 1%. These results enable the preparation of 86Y radiopharmaceuticals for 86Y/90Y-based cancer theranostic applications. Highlights • Simple radiochemical separation using single column extraction chromatography. • Separation strategy for production of high-quality theranostic Y-86 applications. • Process allows for high recycling efficiency of the enriched target material. [ABSTRACT FROM AUTHOR]

Abstract Introduction The remarkable stability of the 89Zr-DOTA complex has been shown in recent literature. The formation of this complex appears to require 89Zr-chloride as the complexation precursor rather than the more conventional 89Zr-oxalate. In this work we present a method for the direct isolation of 89Zr-chloride from irradiated natY foils. Methods 89Zr, 88Zr, and 88Y were prepared by 16 MeV proton irradiation of natY foils and used for batch-extraction based equilibrium coefficient measurements for TBP and UTEVA resin. Radionuclidically pure 89Zr was prepared by 14 MeV proton-irradiation of natY foils. These foils were dissolved in concentrated HCl, trapped on columns of TBP or UTEVA resin, and 89Zr-chloride was eluted in <1 mL of 0.1 M HCl. For purposes of comparison, conventionally-isolated 89Zr-oxalate was converted to 89Zr-chloride by trapping, rinsing, and elution from a QMA cartridge into 1 M HCl. Trace metal analysis was performed on the resulting 89Zr products. Results Equilibrium coefficients for Y and Zr were similar between UTEVA and TBP resins across all HCl concentrations. K d values of <10−1 mL/g were observed for Y across all HCl concentrations. K d values of >103 mL/g were observed at HCl concentrations >9 M for Zr, falling to K d values of <100 mL/g at low HCl concentrations. 89Zr-chloride was recovered from small columns of TBP in <1 mL of 0.1 M HCl with an overall recovery efficiency of 89 ± 3% (n = 3). An average Y/Zr separation factor of 1.5 × 105 (n = 3) was obtained. Trace metal impurities, notably Fe, were higher in TBP-isolated 89Zr-chloride compared with 89Zr-chloride prepared using the conventional two-step procedure. Conclusion TBP-functionalized resin appears promising for the direct isolation of 89Zr-chloride from irradiated natY targets. Excellent 89Zr recovery efficiencies were obtained, and chemical purity was sufficient for proof-of-concept chelation studies. [ABSTRACT FROM AUTHOR]

Targeted Meitner-Auger Therapy (TMAT) has potential for personalized treatment thanks to its subcellular dosimetric selectivity, which is distinct from the dosimetry of β − and α particle emission based Targeted Radionuclide Therapy (TRT). To date, most clinical and preclinical TMAT studies have used commercially available radionuclides. These studies showed promising results despite using radionuclides with theoretically suboptimal photon to electron ratios, decay kinetics, and electron emission spectra. Studies using radionuclides whose decay characteristics are considered more optimal are therefore important for evaluation of the full potential of Meitner-Auger therapy; 119Sb is among the best such candidates. In the present work, we develop radiochemical purification of 120Sb from irradiated natural tin targets for TMAT studies with 119Sb. [Display omitted] [ABSTRACT FROM AUTHOR]

Radiolabeled nanoprobes for positron emission tomography (PET) imaging has received special attention over the past decade, allowing for sensitive, non-invasive, and quantitative detection of different diseases. The rapidly renal clearable nanomaterials normally suffer from a low accumulation in the tumor through the enhanced permeability and retention (EPR) effect due to the rapidly reduced concentration in the blood circulation after renal clearance. It is highly important to design radiolabeled nanomaterials which can meet the balance between the rapid renal clearance and strong EPR effect within a suitable timescale. Herein, renal clearable polyoxometalate (POM) clusters of ultra-small size (∼1 nm in diameter) were readily radiolabeled with the oxophilic 89 Zr to obtain 89 Zr-POM clusters, which may allow for efficient staging of kidney dysfunction in a murine model of unilateral ureteral obstruction (UUO). Furthermore, the as-synthesized clusters can accumulate in the tumor through EPR effect and self-assemble into larger nanostructures in the acidic tumor microenvironment for enhanced tumor accumulation, offering an excellent balance between renal clearance and EPR effect. [ABSTRACT FROM AUTHOR]

Purpose: CD38 is considered a potential biomarker for multiple myeloma (MM) and has shown a strong link with chronic lymphocytic leukemia due to high and uniform expression on plasma cells. In vivo evaluation of CD38 expression may provide useful information about lesion detection and prognosis of treatment in MM. In this study, immunoPET imaging with 89Zr-labeled daratumumab was used for differentiation of CD38 expression in murine lymphoma models to provide a potential non-invasive method for monitoring CD38 in the clinic.Methods: Daratumumab was radiolabeled with 89Zr (t1/2 = 78.4 h) via conjugation with desferrioxamine (Df). After Western blot (WB) was used to screen CD38 expression in five lymphoma cell lines, flow cytometry and cellular binding assays were performed to test the binding ability of labeled or conjugated daratumumab with CD38 in vitro. PET imaging and biodistribution studies were performed to evaluate CD38 expression after injection of 89Zr-Df-daratumumab. 89Zr-Df-IgG was also evaluated as a non-specific control group in the Ramos model. Finally, CD38 expression in tumor tissues was verified by histological analysis.Results: Using WB screening, the Ramos cell line was found to express the highest level of CD38 while the HBL-1 cell line had the lowest expression. Df-conjugated and 89Zr-labeled daratumumab displayed similar high binding affinities with Ramos cells. PET imaging of 89Zr-Df-daratumumab showed a high tumor uptake of up to 26.6 ± 8.0 %ID/g for Ramos at 120 h post-injection, and only up to 6.6 ± 2.9 %ID/g for HBL-1 (n = 4). Additionally, 89Zr-Df-IgG demonstrated a low tumor uptake in the Ramos model (only 4.3 ± 0.8 %ID/g at 120 h post-injection). Ex vivo biodistribution studies showed similar trends with imaging results. Immunofluorescence staining of tumor tissues verified higher CD38 expression of Ramos than that of HBL-1.Conclusions: The role of 89Zr-Df-daratumumab was investigated for evaluating CD38 expression in lymphoma models non-invasively and was found to be to a promising imaging agent of CD38-positive hematological diseases such as MM in future clinical applications. [ABSTRACT FROM AUTHOR]

Mesoporous silica nanoshell (MSN) coating has been demonstrated as a versatile surface modification strategy for various kinds of inorganic functional nanoparticles, such as gold nanorods (GNRs), to achieve not only improved nanoparticle stability but also concomitant drug loading capability. However, limited drug loading capacity and low tumor accumulation rate in vivo are two major challenges for the biomedical applications of MSN-coated GNRs (GNR@MSN). In this study, by coating uniformly sized GNRs with MSN in an oil-water biphase reaction system, we have successfully synthesized a new bacteria-like GNR@MSN (i.e., bGNR@MSN) with a significantly enlarged pore size (4–8 nm) and surface area (470 m 2 /g). After PEGylation and highly efficient loading of doxorubicin (DOX, 40.9%, w/w), bGNR@MSN were used for positron emission tomography (PET, via facile and chelator-free 89 Zr-labeling) and photoacoustic imaging-guided chemo-photothermal cancer therapy in vivo . PET imaging showed that 89 Zr-labeled bGNR@MSN(DOX)-PEG can passively target to the 4T1 murine breast cancer-bearing mice with high efficiency (∼10 %ID/g), based on enhanced permeability and retention effect. Significantly enhanced chemo-photothermal combination therapy was also achieved due to excellent photothermal effect and near-infrared-light-triggered drug release by bGNR@MSN(DOX)-PEG at the tumor site. The promising results indicate great potential of bGNR@MSN-PEG nanoplatforms for future cancer diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Background: The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer's disease (AD).Objective: The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD.Methods: Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest.Results: Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume.Conclusions: In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions. [ABSTRACT FROM AUTHOR]

Purpose: Nivolumab is a human monoclonal antibody specific for programmed cell death-1 (PD-1), a negative regulator of T-cell activation and response. Acting as an immune checkpoint inhibitor, nivolumab binds to PD-1 expressed on the surface of many immune cells and prevents ligation by its natural ligands. Nivolumab is only effective in a subset of patients, and there is limited evidence supporting its use for diagnostic, monitoring, or stratification purposes. Methods: Zr-Df-nivolumab was synthesized to map the biodistribution of PD-1-expressing tumor infiltrating T-cells in vivo using a humanized murine model of lung cancer. The tracer was developed by radiolabeling the antibody with the positron emitter zirconium-89 (Zr). Imaging results were validated by ex vivo biodistribution studies, and PD-1 expression was validated by immunohistochemistry. Data obtained from PET imaging were used to determine human dosimetry estimations. Results: The tracer showed elevated binding to stimulated PD-1 expressing T-cells in vitro and in vivo. PET imaging of Zr-Df-nivolumab allowed for clear delineation of subcutaneous tumors through targeting of localized activated T-cells expressing PD-1 in the tumors and salivary glands of humanized A549 tumor-bearing mice. In addition to tumor uptake, salivary and lacrimal gland infiltration of T-cells was noticeably visible and confirmed via histological analysis. Conclusions: These data support our claim that PD-1-targeted agents allow for tumor imaging in vivo, which may assist in the design and development of new immunotherapies. In the future, noninvasive imaging of immunotherapy biomarkers may assist in disease diagnostics, disease monitoring, and patient stratification. [ABSTRACT FROM AUTHOR]

This work characterizes the radiochemical synthesis, purification, and formulation of [ 18 F]THK-5351, a tau PET radioligand, and develops an automated radiosynthesis routine (ELIXYS, Sofie Biosciences). Nucleophilic radiofluorination reaction was complete by 7 min at 110 °C with radiochemical yields proportional to precursor mass (0.1–0.5 mg). Optimized HPLC purification produced radiotracer product with no chemical impurities observed on analytical HPLC in formulation. Automated radiosynthesis (ELIXYS), HPLC purification and formulation was completed in 86 min producing formulated product suitable for human research use. [ABSTRACT FROM AUTHOR]

Overexpression of tissue factor (TF) has been associated with increased tumor growth, tumor angiogenesis, and metastatic potential in many malignancies, including pancreatic cancer. Additionally, high TF expression was shown to strongly correlate with poor prognoses and decreased survival in pancreatic cancer patients. Herein, we exploited the potential targeting of TF for positron emission tomography (PET) imaging of pancreatic cancer. The TF-targeted tracer was developed through radiolabeling of the anti-human TF monoclonal antibody (ALT-836) with 89 Zr. The tracer was characterized by fluorescence microscopy and flow cytometry assays in BXPC-3 and PANC-1 cells, two pancreatic cancer cell lines with high and low TF expression levels, respectively. Non-invasive PET scans were acquired in tumor-bearing mice injected with 89 Zr-Df-ALT-836. Additionally, ex vivo biodistribution, blocking, and histological studies were performed to establish the affinity and specificity of 89 Zr-Df-ALT-836 for TF in vivo . 89 Zr-labeling of Df-ALT-836 was achieved in high yield and good specific activity. Flow cytometry and microscopy studies revealed no detectable difference in TF-binding affinity between ALT-836 and Df-ALT-836 in vitro . Longitudinal PET scans unveiled a lasting and prominent 89 Zr-Df-ALT-836 uptake in BXPC-3 tumors (peak at 31.5 ± 6.0%ID/g at 48 h post-injection; n = 3), which was significantly abrogated (2.3 ± 0.5%ID/g at 48 h post-injection; n = 3) when mice were pre-injected with a blocking dose (50 mg/kg) of unlabeled ALT-836. Ex vivo biodistribution data confirmed the accuracy of the PET results, and histological analysis correlated high tumor uptake with in situ TF expression. Taken together, these results attest to the excellent affinity and TF-specificity of 89 Zr-Df-ALT-836. With elevated, persistent, and specific accumulation in TF-positive BXPC-3 tumors, PET imaging using 89 Zr-Df-ALT-836 promises to open new avenues for improving future diagnosis, stratification, and treatment response assessment in pancreatic cancer patients. [ABSTRACT FROM AUTHOR]

Nanomaterials with renal clearance from the body within a reasonable timescale have shown great promises in the area of nanomedicine recently. However, the integration of theranostic and renal clearance properties into a single ultrasmall nanostructure remains a great challenge. Herein, meso-tetra(4-carboxyphenyl)porphyrin (TCPP) structure is utilized as a model, for the first time using noninvasive dynamic positron emission tomography (PET) imaging to investigate the balance of the renal clearance and tumor uptake behaviors of polyethylene glycol (PEG)-modified porphyrin nanoparticles (TCPP-PEG) with various molecular weights. This study finds that TCPP-PEG nanoparticles with larger molecular weight show higher tumor uptake due to the enhanced permeability and retention effect, while the lower ones tend to be better for renal clearance. Based on dynamic PET and fluorescence dual-modal imaging modalities, the TCPP-PEG10K nanoparticles seem to be an excellent choice for the balance of renal clearance and tumor retention. In vitro and in vivo photodynamic therapy confirms an excellent therapeutic efficacy. Therefore, this work presents a simplified approach to fabricate and select biocompatible multifunctional TCPP-PEG-based theranostic agents with renal clearance behavior, which highlights the clinical application potential of TCPP-PEG nanoparticles as theranostic probes for imaging-guided cancer therapy. [ABSTRACT FROM AUTHOR]

The noninvasive measurement of functional β-cell mass would be clinically valuable for monitoring the progression of type 1 and type 2 diabetes as well as the viability of transplanted insulin-producing cells. Although previous work using MRI has shown promise for functional β-cell mass determination through voltage-dependent Ca2+ channel (VDCC)-mediated internalization of Mn2+, the clinical utility of this technique is limited by the cytotoxic levels of the Mn2+ contrast agent. Here, we show that positron emission tomography (PET) is advantageous for determining functional β-cell mass using 52Mn2+ (t1/2: 5.6 days). We investigated the whole-body distribution of 52Mn2+ in healthy adult mice by dynamic and static PET imaging. Pancreatic VDCC uptake of 52Mn2+ was successfully manipulated pharmacologically in vitro and in vivo using glucose, nifedipine (VDCC blocker), the sulfonylureas tolbutamide and glibenclamide (KATP channel blockers), and diazoxide (KATP channel opener). In a mouse model of streptozotocin-induced type 1 diabetes, 52Mn2+ uptake in the pancreas was distinguished from healthy controls in parallel with classic histological quantification of β-cell mass from pancreatic sections. 52Mn2+-PET also reported the expected increase in functional β-cell mass in the ob/ob model of pretype 2 diabetes, a result corroborated by histological β-cell mass measurements and live-cell imaging of β-cell Ca2+ oscillations. These results indicate that 52Mn2+-PET is a sensitive new tool for the noninvasive assessment of functional β-cell mass. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the suitability of [18 F]nifene, a novel α4β2* nicotinic acetylcholine receptor (nAChR) radiotracer, for in vivo brain imaging in a first-in-human study. Methods: Eight healthy subjects (4 M,4 F;21-69,44 ± 21 yrs) underwent a [18F]nifene positron emission tomography scan (200 ± 3.7 MBq), and seven underwent a second scan within 58 ± 31 days. Regional estimates of DVR were measured using the multilinear reference tissue model (MRTM2) with the corpus callosum as reference region. DVR reproducibility was evaluated with test-retest variability (TRV) and intraclass correlation coefficient (ICC). Results: The DVR ranged from 1.3 to 2.5 across brain regions with a TRV of 0-7%, and did not demonstrate a systematic difference between test and retest. The ICCs ranged from 0.2 to 0.9. DVR estimates were stable after 40 min. Conclusion: The binding profile and tracer kinetics of [18F]nifene make it a promising α4β2* nAChR radiotracer for scientific research in humans, with reliable DVR test-retest reproducibility. [ABSTRACT FROM AUTHOR]

Neurotensin receptor 1 (NTSR1) can stimulate tumor proliferation through neurotensin (NTS) activation and are overexpressed by a variety of cancers. The high binding affinity of NTS/NTSR1 makes radiolabeled NTS derivatives interesting for cancer diagnosis and staging. Internalization of NTS/NTSR1 also suggests therapeutic application with high LET alpha particles and low energy electrons. We investigated the therapeutic efficacy of [58mCo]Co-NOTA-NT-20.3 in vivo using murine models xenografted with NTSR1-positive HT29 human colorectal adenocarcinoma cells, and utilized [55Co]Co-NOTA-NT-20.3 for dosimetry. Targeting properties and cytotoxicity of [55/58mCo]Co-NOTA-NT-20.3 were assessed with HT29 cells. Female nude mice were xenografted with HT29 tumors and administered [55Co or 58mCo]Co-NOTA-NT-20.3 to evaluate pharmacokinetics or for therapy, respectively. Dosimetry calculations followed the Medical Internal Radiation Dose (MIRD) formalism and human absorbed dose rate per unit activity were obtained from OpenDose. The pilot therapy study consisted of two groups (each N = 3) receiving 110 ± 15 MBq and 26 ± 6 MBq [58mCo]Co-NOTA-NT-20.3 one week after tumor inoculation, and control (N = 3). Tumor sizes and masses were measured twice a week after therapy. Complete blood count and kidney histology were also performed to assess toxicity. HPLC measured radiochemical purity of [55,58mCo]Co-NOTA-NT-20.3 > 99 %. Labeled compounds retained NTS targeting properties. [58mCo]Co-NOTA-NT-20.3 exhibited cytotoxicity for HT29 cells and was >15× more potent than [58mCo]CoCl 2. Xenografted tumors responded modestly to administered doses, but mice showed no signs of radiotoxicity. Absorbed dose to tumor and kidney with 110 MBq [58mCo]Co-NOTA-NT-20.3 were 0.6 Gy and 0.8 Gy, respectively, and other organs received less than half of the absorbed dose to tumor. Off-target radiation dose from cobalt-58g was small but reduces the therapeutic window. The enhanced in vitro cytotoxicity and high tumor-to-background led us to investigate the therapeutic efficacy of [58mCo]Co-NOTA-NT-20.3 in vivo. Although we were unable to induce tumor response commensurate with [177Lu]Lu-NT127 (NLys-Lys-Pro-Tyr-Tle-Leu) studies involving similar time-integrated activity, the absence of observed toxicity may constitute an opportunity for targeting vectors with improved uptake and/or retention to avoid the aftereffects of other high-LET radioactive emissions. Future studies with higher uptake, activity and/or multiple dosing regimens are warranted. The theranostic approach employed in this work was crucial for dosimetry analysis. [Display omitted] • First in vivo therapy study of 58mCo with an internalizing targeting vector • [58mCo]Co-NOTA-NT-20.3 was >15× more cytotoxic to HT29 cells in vitro than [58mCo]CoCl 2. • Theranostic approach with 55Co enabled visualization of tumor uptake and dosimetry. [ABSTRACT FROM AUTHOR]

Although various types of imaging agents have been developed for photoacoustic (PA) imaging, relatively few imaging agents exhibit high selectivity/sensitivity to the tumor microenvironment for on-demand PA imaging and therapy. Herein, molybdenum-based polyoxometalate (POM) clusters with the highest oxidation state of Mo(VI) (denoted as Ox-POM) were designed as novel agents for redox-activated PA imaging-guided photothermal therapy. Capable of escaping from recognition and capture by the liver and spleen, these renal clearable clusters with ultrasmall size (hydrodynamic size: 1.9 nm) can accumulate in the tumor, self-assemble into larger nanoclusters at low pH, and are reduced to NIR absorptive agents in the tumor microenvironment. Studies in 4T1 tumor-bearing mice indicated that these clusters could be employed for bioresponsive PA imaging-guided tumor ablation in vivo. Our finding is expected to establish a new physicochemical paradigm for the design of PA imaging agents based on clusters, bridging the conventional concepts of "molecule" and "nano" in the bioimaging field. [ABSTRACT FROM AUTHOR]

Zirconium-89 finds broad application for use in positron emission tomography. Its cyclotron production has been limited by the heat transfer from yttrium targets at high beam currents. A spot welding technique allows a three-fold increase in beam current, without affecting 89 Zr quality. An yttrium foil, welded to a jet-cooled tantalum support base accommodates a 50 µA proton beam degraded to 14 MeV. The resulting activity yield of 48±4 MBq/(μA∙hr) now extends the outreach of 89 Zr for a broader distribution. [ABSTRACT FROM AUTHOR]

Multifunctional theranostic agents have become rather attractive to realize image-guided combination cancer therapy. Herein, a novel method is developed to synthesize Bi2Se3 nanosheets decorated with mono-dispersed FeSe2 nanoparticles (FeSe2/Bi2Se3) for tetra-modal image-guided combined photothermal and radiation tumor therapy. Interestingly, upon addition of Bi(NO3)3, pre-made FeSe2 nanoparticles via cation exchange would be gradually converted into Bi2Se3 nanosheets, on which remaining FeSe2 nanoparticles are decorated. The yielded FeSe2/Bi2Se3 composite-nanostructures are then modified with polyethylene glycol (PEG). Taking advantages of the high r2 relaxivity of FeSe2, the X-ray attenuation ability of Bi2Se3, the strong near-infrared optical absorbance of the whole nanostructure, as well as the chelate-free radiolabeling of 64Cu on FeSe2/Bi2Se3-PEG, in vivo magnetic resonance/computer tomography/photoacoustic/position emission tomography multimodal imaging is carried out, revealing efficient tumor homing of FeSe2/Bi2Se3-PEG after intravenous injection. Utilizing the intrinsic physical properties of FeSe2/Bi2Se3-PEG, in vivo photothermal and radiation therapy to achieve synergistic tumor destruction is then realized, without causing obvious toxicity to the treated animals. This work presents a unique method to synthesize composite-nanostructures with highly integrated functionalities, promising not only for nano-biomedicine but also potentially for other different nanotechnology fields. [ABSTRACT FROM AUTHOR]

• Experimental measurement of 54Fe(p, α)51Mn cross section from 9.5 to 18 MeV E 0 , p + . • Radioisotopic and radionuclidic purities >99.9% near end of bombardment. • End of bombardment yield >3.5 GBq from 100 mg/cm254Fe target and 40 μAh (40 μA, 1 h). • Validation of 51Mn production from 54Fe(p, α)51Mn for future clinical needs. • Final relative uncertainties within ±12%. Excitation function of the 54Fe(p, α)51Mn reaction was measured from 9.5 to 18 MeV E 0 , p + by activating a foil stack of 54Fe electrodeposited on copper substrates. Residual radionuclides were quantified by HPGe gamma ray spectrometry. Both 51Mn (t 1 / 2 = 46.2 min , 〈 E β + 〉 = 963.7 keV, I β + = 97 %; E γ = 749.1 keV, I γ = 0.265 %) and its radioactive daughter, 51Cr (t 1 / 2 = 27.704 d, E γ = 320.1 keV, I γ = 9.91 %), were used to indirectly quantify formation of 51Mn. Results agree within uncertainty to the only other measurement in literature and predictions of default TALYS theoretical code. Final relative uncertainties are within ±12%. [ABSTRACT FROM AUTHOR]

Background: Ion transport is a fundamental physiological process that can be studied non-invasively in living plants with radiotracer imaging methods. Fluoride is a known phytotoxic pollutant and understanding its transport in plants after leaf absorption is of interest to those in agricultural areas near industrial sources of airborne fluoride. Here we report the novel use of a commercial, high-resolution, animal positron emission tomography (PET) scanner to trace a bolus of [18F]fluoride administered via bisected petioles of Brassica oleracea, an established model species, to simulate whole plant uptake of atmospheric fluoride. This methodology allows for the first time mathematical compartmental modeling of fluoride transport in the living plant. Radiotracer kinetics in the stem were described with a single-parameter free- and trapped-compartment model and mean arrival times at different stem positions were calculated from the free-compartment time-activity curves. Results: After initiation of administration at the bisected leaf stalk, [18F] radioactivity climbed for approximately 10 minutes followed by rapid washout from the stem and equilibration within leaves. Kinetic modeling of transport in the stem yielded a trapping rate of 1.5 +/- 0.3%/min (mean +/- s.d., n = 3), velocity of 2.2 +/- 1.1 cm/min, and trapping fraction of 0.8 +/- 0.5%/cm. Conclusion: Quantitative assessment of physiologically meaningful transport parameters of fluoride in living plants is possible using standard positron emission tomography in combination with petiolar radiotracer administration. Movement of free fluoride was observed to be consistent with bulk flow in xylem, namely a rapid and linear change in position with respect to time. Trapping, likely in the apoplast, was observed. Future applications of the methods described here include studies of transport of other ions and molecules of interest in plant physiology. [ABSTRACT FROM AUTHOR]

Although graphene oxide (GO) has recently been considered as a highly attractive nanomaterial for future cancer imaging and therapy, it is still a major challenge to improve its in vivo tumor active targeting efficiency. Here in this full article, we demonstrated the successful and significantly enhanced in vivo tumor vasculature targeting efficacy of well-functionalized GO nanoconjugates by using vascular endothelial growth factor 121 (VEGF121) as the targeting ligand. As-developed GO nanoconjugate exhibits excellent in vivo stability, specific in vitro and in vivo vascular endothelial growth factor receptor (VEGFR) targeting, significantly enhanced tumor accumulation (>8 %ID/g) as well as high tumor-to-muscle contrast, showing great potential for future tumor targeted imaging and therapy. [ABSTRACT FROM AUTHOR]

Background We examined the effects of moderate prenatal alcohol exposure and/or prenatal stress exposure on (D1R) binding in a non human primate model. The dopamine D1R is involved in executive function, and it may play a role in cognitive behavioral deficits associated with prenatal alcohol and/or stress exposure. Little is known, however, about the effects of prenatal alcohol and/or stress exposure on the D1R. We expected that prenatal insults would lead to alterations in D1R binding in prefrontal cortex (PFC) and striatum in adulthood. Methods Rhesus macaque females were randomly assigned to moderate alcohol exposure and/or mild prenatal stress as well as a control condition during pregnancy. Thirty-eight offspring were raised identically and studied as adults by noninvasive in vivo neuroimaging using positron emission tomography with the D1 antagonist radiotracer [11C]SCH 23390. Radiotracer binding in PFC and striatum was evaluated by 2 (alcohol) × 2 (stress) × 2 (sex) analysis of variance. Results In PFC, a significant alcohol × sex interaction was observed with prenatal alcohol exposure leading to increased [11C]SCH 23390 binding in male monkeys. No main effect of prenatal alcohol or prenatal stress exposure was observed. Conclusions These results suggest that prenatal alcohol exposure results in long-term increases in prefrontal dopamine D1R binding in males. This may help explain gender differences in the prevalence of neurodevelopmental disorders consequent to prenatal alcohol exposure. [ABSTRACT FROM AUTHOR]

Background Previous studies have found interrelationships between the serotonin system and alcohol self-administration. The goal of this work was to directly observe in vivo effects of chronic ethanol self-administration on serotonin 5-HT 1A receptor binding with [ 18 F]mefway PET neuroimaging in rhesus monkeys. Subjects were first imaged alcohol-naïve and again during chronic ethanol self-administration to quantify changes in 5-HT 1A receptor binding. Methods Fourteen rhesus monkey subjects (10.7–12.8 years) underwent baseline [ 18 F]mefway PET scans prior to alcohol exposure. Subjects then drank gradually increasing ethanol doses over four months as an induction period, immediately followed by at least nine months ad libidum ethanol access. A post [ 18 F]mefway PET scan was acquired during the final three months of ad libidum ethanol self-administration. 5-HT 1A receptor binding was assayed with binding potential ( BP ND ) using the cerebellum as a reference region. Changes in 5-HT 1A binding during chronic ethanol self-administration were examined. Relationships of binding metrics with daily ethanol self-administration were also assessed. Results Widespread increases in 5-HT 1A binding were observed during chronic ethanol self-administration, independent of the amount of ethanol consumed. A positive correlation between 5-HT 1A binding in the raphe nuclei and average daily ethanol self-administration was also observed, indicating that baseline 5-HT 1A binding in this region predicted drinking levels. Conclusions The increase in 5-HT 1A binding levels during chronic ethanol self-administration demonstrates an important modulation of the serotonin system due to chronic alcohol exposure. Furthermore, the correlation between 5-HT 1A binding in the raphe nuclei and daily ethanol self-administration indicates a relationship between the serotonin system and alcohol self-administration. [ABSTRACT FROM AUTHOR]

There is a need for safer and improved methods for non-invasive imaging of the gastrointestinal tract. Modalities based on X-ray radiation, magnetic resonance and ultrasound suffer from limitations with respect to safety, accessibility or lack of adequate contrast. Functional intestinal imaging of dynamic gut processes has not been practical using existing approaches. Here, we report the development of a family of nanoparticles that can withstand the harsh conditions of the stomach and intestine, avoid systemic absorption, and provide good optical contrast for photoacoustic imaging. The hydrophobicity of naphthalocyanine dyes was exploited to generate purified ∼20 nm frozen micelles, which we call nanonaps, with tunable and large near-infrared absorption values (>1,000). Unlike conventional chromophores, nanonaps exhibit non-shifting spectra at ultrahigh optical densities and, following oral administration in mice, passed safely through the gastrointestinal tract. Non-invasive, non-ionizing photoacoustic techniques were used to visualize nanonap intestinal distribution with low background and remarkable resolution, and enabled real-time intestinal functional imaging with ultrasound co-registration. Positron emission tomography following seamless nanonap radiolabelling allowed complementary whole-body imaging. [ABSTRACT FROM AUTHOR]