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The fields of nuclear medicine and molecular imaging include a wealth of different technologies and methodologies, that go beyond PET and SPECT imaging devices and radiopharmaceuticals. With the increasing insight into the complexity of diseases along with the growing number of options for treatments, molecular imaging is needed to improve the in vivo phenotyping of diseases and to support the shift toward personalized medicine, i.e., tailored therapeutic strategies. PET: the merging of biology and imaging into molecular imaging. [Extracted from the article]

Of course, this generates eye-catchingly high absolute tumor uptake and striking tumor/non-tumor ratios, but generates data with no true predictive value for the human situation and leads to an overestimation of tracer performance [[3]]. In a mouse, the same tumor - and tumors frequently reach that size in therapy studies - corresponds to 1/25 of TBW. This, in our view, generally challenges the usefulness of radioligand therapy studies in mice, especially in the light of the excellent and constantly improving dosimetry extrapolations from mice to humans. [Extracted from the article]

Due to successes in the development on new and powerful radiopharmaceuticals, in particular of tracers for positron emission tomography, the production of a continuously expanding spectrum of radiopharmaceuticals has become more important, even for small nuclear medicine facilities. This short review summarizes and briefly describes typically established radioanalytical routines in the quality control of radiopharmaceuticals as well as the corresponding fundamental legal documents and guidelines. [ABSTRACT FROM AUTHOR]

Background: The chemokine receptor 4 (CXCR4) is an important molecular target for both visualization and therapy of tumors. The aim of the present study was the synthesis and preclinical evaluation of a Cu-labeled, CXCR4-targeting peptide for positron emission tomography (PET) imaging of CXCR4 expression in vivo. Methods: For this purpose, 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), or 1,4,7-triazacyclononane-triacetic acid (NOTA) was conjugated to the highly affine CXCR4-targeting pentixather scaffold. Affinities were determined using Jurkat T-lymphocytes in competitive binding assays employing [I]FC131 as the radioligand. Internalization and efflux studies of [Cu]NOTA-pentixather were performed in chem-1 cells, stably transfected with hCXCR4. The stability of the tracer was evaluated in vitro and in vivo . Small-animal PET and biodistribution studies at different time points were performed in Daudi lymphoma-bearing severe combined immunodeficiency (SCID) mice. Results: [Cu]NOTA-pentixather was rapidly radiolabeled at 60 °C with high radiochemical yields ≥90% and purities >99%. [Cu]NOTA-pentixather offered the highest affinity of the evaluated peptides in this study (IC = 14.9 ± 2.1 nM), showed efficient CXCR4-targeting in vitro and was stable in blood and urine with high resistance to transchelation in ethylenediaminetetraacetic acid (EDTA) challenge studies. Due to the enhanced lipophilicity of [Cu]NOTA-pentixather (logP = -1.2), biodistribution studies showed some nonspecific accumulation in the liver and intestines. However, tumor accumulation (13.1 ± 1.5% ID/g, 1.5 h p.i.) was CXCR4-specific and higher than in all other organs and resulted in high resolution delineation of Daudi tumors in PET/CT images in vivo. Conclusions: [Cu]NOTA-pentixather was fast and efficiently radiolabeled, showed effective CXCR4-targeting, high stability in vitro and in vivo and resulted in high resolution PET/CT images accompanied with a suitable biodistribution profile, making [Cu]NOTA-pentixather a promising tracer for future application in humans. [ABSTRACT FROM AUTHOR]

Background: Due to its overexpression in a variety of tumor types, the chemokine receptor 4 (CXCR4) represents a highly relevant diagnostic and therapeutic target in nuclear oncology. Recently, [Ga]pentixafor has emerged as an excellent imaging agent for positron emission tomography (PET) of CXCR4 expression in vivo. In this study, the corresponding [Ga]-1,4,7-triazacyclononane-triacetic acid (NOTA) analog was preclinically evaluated and compared to the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) parent compound [Ga]pentixafor. Methods: NOTA-pentixafor was synthesized by combining solid and solution-phase peptide synthesis. The CXCR4 receptor affinities of [Ga]pentixafor and [Ga]NOTA-pentixafor were determined in competitive binding assays using the leukemic CXCR4-expressing Jurkat T-cell line and [I]FC131 as the radioligand. Internalization and cell efflux assays were performed using CXCR4-transfected Chem-1 cells. Small-animal PET and biodistribution studies were carried out using Daudi-tumor bearing SCID mice. Results: [Ga]NOTA-pentixafor showed a 1.4-fold improved affinity towards CXCR4 (IC). However, internalization efficiency into CXCR4-Chem-1 cells was substantially decreased compared to [Ga]pentixafor. Accordingly, small-animal PET imaging and biodistribution studies revealed a 9.5-fold decreased uptake of [Ga]NOTA-pentixafor in Daudi lymphoma xenografts (1.7 ± 0.4 % vs 16.2 ± 3.8 % ID/g at 90 min p.i.) and higher levels of non-specific accumulation, primarily in the excretory organs such as the liver, intestines, and kidneys (2.3 ± 0.9 % vs 2.0 ± 0.3 % ID/g, 1.9 ± 0.8 % vs 0.7 ± 0.2 % ID/g, and 2.7 ± 1.1 % vs 1.7 ± 0.9 % ID/g, respectively). Conclusions: Despite enhanced CXCR4-affinity in vitro, the [Ga]NOTA-analog of pentixafor showed reduced CXCR4 targeting efficiency in vivo. In combination with enhanced background accumulation, this resulted in significantly inferior PET imaging contrast, and thus, [Ga]NOTA-pentixafor offers no advantages over [Ga]pentixafor. [ABSTRACT FROM AUTHOR]

Background: The overexpression of the chemokine receptor 4 (CXCR4) in different epithelial, mesenchymal, and hematopoietic cancers makes CXCR4 an attractive diagnostic and therapeutic target. However, targeting the CXCR4 receptor with small cyclic pentapeptide-based radiopharmaceuticals remains challenging because minor structural modifications within the ligand-linker-chelate structure often significantly affect the receptor affinity. Based on the excellent in vivo properties of CXCR4-directed pentapeptide [Ga]pentixafor (cyclo(- d-Tyr- N-Me- d-Orn(AMB-DOTA)- l-Arg- l-2-Nal-Gly-)), this study aims to broaden the spectrum of applicable (radio)metal-labeled pentixafor analogs. Methods: Cyclic pentapeptides, based on the pentixafor scaffold, were synthesized by a combined solid- and solution-phase peptide synthesis. The CXCR4 receptor affinities of the cold reference compounds were determined in competitive binding assays using CXCR4-expressing Jurkat T - cell leukemia cells and [I]FC131 as the radioligand. Results: Metalated pentixafor derivatives with cyclic and acyclic chelators were synthesized by solid-phase peptide synthesis and evaluated in vitro. The resulting CXCR4 affinities (IC) were highly dependent on the chelator and metal used. Two pentapeptides, Ga-NOTA and Bi-DOTA conjugates, offer an improved affinity compared to [Ga]pentixafor. Conclusions: Based on the pentapeptide [Ga]pentixafor, a broad range of metal-labeled analogs were investigated. The affinities of the new compounds were found to be strongly dependent on both the chelator and the metal used. Bi-labeled pentixafor showed high receptor affinity and seems to be a promising ligand for further preclinical evaluation and future α-emitter-based endoradiotherapy. [ABSTRACT FROM AUTHOR]

Usually, the accessibility of 3-iodo-Tyr-containing peptides relies on the time-consuming de novo solid phase peptide synthesis. In this study, methods for the direct (mono)iodination of unprotected peptides were evaluated. The use of N -iodosuccinimide (NIS) in acetonitrile/water proved to be a particularly mild, fast (⩽5 min) and efficient method with broad applicability to structurally diverse peptides. NIS iodination therefore represents a very practicable tool for the generation of iodinated peptides on a small (<1 mg) to medium (1–20 mg) scale in reasonable isolated yields (28 ± 8%), providing easy and straightforward access to iodinated reference compounds, for example, for in vitro evaluation. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a downstream molecule of p38, involved in the production of TNF-α, a key cytokine, and an established drug target for many inflammatory diseases. We investigated the role of MK2 in skin inflammation to determine its drug target potential. MK2 deficiency significantly decreased plasma TNF-α levels after systemic endotoxin application. Deficient mice showed decreased skin edema formation in chronic 2-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritative dermatitis and in subacute 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity. Surprisingly, MK2 deficiency did not inhibit edema formation in subacute 2,4-dinitrochlorobenzene (DNCB)-induced contact allergy and even increased TNF-α and IL-1β levels as well as granulocyte infiltration in diseased ears. Ear inflammation in this model, however, was inhibited by TNF-α neutralization as it was in the subacute DNFB model. MK2 deficiency also did not show anti-inflammatory effects in acute DNFB-induced contact hypersensitivity, whereas the p38 inhibitor, SB203580, ameliorated skin inflammation supporting a pathophysiological role of p38. When evaluating possible mechanisms, we found that TNF-α production in MK2-deficient spleen cells was strongly diminished after TLR stimulation but less affected after T-cell receptor stimulation. Our data suggest that MK2, in contrast to its downstream effector molecule, TNF-α, has a rather elusive role in T-cell-dependent cutaneous inflammation. [ABSTRACT FROM AUTHOR]

Oxime formation between an aminooxy-functionalized peptide and an 18F-labelled aldehyde has recently been introduced as a powerful method for the rapid one-step chemoselective synthesis of radiofluorinated peptides. Here, the potential of using routinely produced and thus readily available [18F]fluorodeoxyglucose ([18F]FDG) as the aldehydic prosthetic group was investigated using an aminooxyacetyl-conjugated cyclic RGD peptide (cyclo(RGDfK(Aoa-(Boc)) as a model peptide. The use of [18F]FDG from routine production ([18F]FDGTUM) containing an excess of d-glucose did not allow the radiosynthesis of [18F]FDG-RGD in activities >37 MBq in reasonable yield, rendering the direct use of clinical grade [18F]FDG for the routine clinical synthesis of 18F-labelled peptides impossible. Using no-carrier-added (n.c.a.) [18F]FDG obtained via HPLC separation of [18F]FDGTUM from excess glucose, however, afforded [18F]FDG-RGD in yields of 56–93% (decay corrected) and activities up to 37 MBq. Suitable reaction conditions were 20 min at 120°C and pH 2.5, and a peptide concentration of 5 m M. In a preliminary in vivo biodistribution study in M21 melanoma-bearing nude mice, [18F]FDG-RGD showed increased tumour accumulation compared to the “gold standard” [18F]galacto-RGD (2.18 vs 1.49 %iD/g, respectively, at 120 min after injection), but also slightly increased uptake in non-target organs, leading to comparable tumour/organ ratios for both compounds. These data demonstrate that chemoselective 18F-labelling of aminooxy-functionalized peptides using n.c.a. [18F]FDG represents a radiofluorination/glycosylation strategy that allows preparation of 18F-labelled peptides in high yield with suitable pharmacokinetics. As soon as the necessary n.c.a. preparation of [18F]FDG prior to reaction with the Aoa-peptide can be implemented in a fully automated [18F]FDG-synthesis, [18F]fluoroglucosylation of peptides may represent a promising alternative to currently used chemoselective one-step 18F-labelling protocols. [ABSTRACT FROM AUTHOR]

Abstract: Overexpressed neuropeptide receptors allow tumor visualization using e.g. radiolabeled peptidic receptor ligands and positron emission tomography (PET) or single photon emission computed tomography (SPECT). This review summarizes the development of radiolabeled probes for peptide receptor imaging since the emergence of the technology with a particular focus on peptide radiopharmaceuticals developed during the last 5 years, and highlights the different factors which are decisive during the process of tracer development and evaluation. [Copyright &y& Elsevier]

Purpose: The future significance of peptide radiopharmaceuticals in diagnostic imaging with PET will be dependent on methodological aspects, as well as other requirements such as availability of the radionuclide and cost-effectiveness of its production. The aim of this study was to evaluate whether recent improvements in the modification of peptide pharmacokinetics by carbohydration may open a niche for the use of 11C-labelled peptide receptor binding tracers. Methods: A carbohydrated analogue of Tyr3-octreotate was used as a clinically relevant peptide. Oxime-mediated coupling between 4-[11C]methoxy-benzaldehyde and an aminooxy-conjugated peptide precursor provided the 11C-labelled peptide in 21±5% decay-corrected yield (n=4) in a synthesis time of about 1 h. Results: In rat pancreas carcinoma xenografted mice, the compound displayed predominant and fast renal clearance combined with high tumour uptake (18.5±2.8% ID/g) at 30 min post injection. Corresponding values for kidney, liver and intestine were 18.5±2.4% ID/g, 3.2±0.5% ID/g and 2.1±0.3% ID/g, respectively. In a PET study with xenografted mice, the tumour (0.2–0.3 g) was clearly delineated as early as 20 min after injection. Somatostatin receptor (sstr)-specific uptake was demonstrated by reduction of tumour uptake to 20% of control by co-injection of TOC (0.4 mg/kg; 30 min p.i.). Conclusion: A 11C-labelled octreotate derivative has been prepared which shows suitable pharmacokinetics for in vivo imaging of sstr-overexpressing tumours and thus represents the first proof of principle for the potential of 11C-labelled peptides in tumour imaging. [ABSTRACT FROM AUTHOR]

During the last decade, peptide radiopharmaceuticals have become an important class of tracers for the detection and localization of malignant neoplasms by peptide receptor imaging (PRI) and for therapeutic intervention by peptide receptor radiotherapy (PRRT). Various radiometalated peptides have entered detailed clinical studies or found broad application for peptide receptor radiotherapy. In contrast, radiohalogenated peptides could not benefit from this development. Especially with respect to the growing number of peptidic structures with high receptor affinity and the increasing demand for means of corresponding receptor status quantification for therapy planning and control, the development of methods for the improved availability of 18F-labeled peptides for positron emission tomography imaging is still a very important objective in radiopharmaceutical research. Consequently, as part of our ongoing efforts in this field, we investigated the potential of carbohydration as a valuable tool to modify pharmacokinetics of peptides and evaluated the influence of this modification on the in vitro and in vivo behavior of octreotide analogs. Furthermore, a new methodology is presented allowing for the fast and straightforward labeling of peptides in a chemoselective manner. This combined approach to the chemoselective conjugation of unprotected, carbohydrated peptides seems to have the potential for a redirection and reevaluation of the future of radiohalogenated peptides in nuclear medicine. [ABSTRACT FROM AUTHOR]

Schottelius AJG, Moldawer LL, Dinarello CA, Asadullah K, Sterry W, Edwards III CK. Biology of tumor necrosis factor-α– implications for psoriasis. Numerous recent investigations have pointed to a key role of the proinflammatory, pleiotropic cytokine tumor necrosis factor-α (TNF-α) in host defense and inflammatory processes. TNF overexpression has been found in lesional skin and in the circulation of psoriatic patients, and it was suggested that TNF-α is crucial in this and other immune diseases. Several approaches to inhibit TNF-α activity have been developed. These include three different neutralizing antibodies to TNF-α as well as three different soluble TNF-α receptors with characteristic properties designed to bind the 17-KDa soluble trimeric TNF-α and the 26-KDa membrane-bound form of TNF-α. Clinical trials have demonstrated significant antipsoriatic effects, and it is likely that blocking TNF-α will become an important therapeutic option. The data available from these trials contribute to further understanding of the disease by demonstrating the major role of TNF-α. An in-depth understanding of the regulation of TNF gene expression, protein production, receptor expression, and signaling pathways may lead to further, potentially important novel therapeutic strategies and antipsoriatic active small molecules, suitable for oral application in the future. Here we review the current knowledge of TNF biology, the approaches to inhibit TNF activity, and their clinical and immunological effects in psoriasis. In addition, the host-defense effects and chronic TNF-blocking activity are discussed. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are the most commonly used antiinflammatory and immunosuppressive drugs. Their outstanding therapeutic effects, however, are often accompanied by severe and sometimes irreversible side effects. For this reason, one goal of research in the GC field is the development of new drugs, which show a reduced side-effect profile while maintaining the antiinflammatory and immunosuppressive properties of classical GCs. GCs affect gene expression by both transactivation and transrepression mechanisms. The antiinflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. Our aim has been to identify ligands of the GC receptor (GR), which preferentially induce transrepression with little or no transactivating activity. Here we describe a nonsteroidal selective GR-agonist, ZK 216348, which shows a significant dissociation between transrepression and transactivation both in vitro and in vivo. In a murine model of skin inflammation, ZK 216348 showed antiinflammatory activity comparable to prednisolone for both systemic and topical application. A markedly superior side-effect profile was found with regard to increases in blood glucose, spleen involution, and, to a lesser extent, skin atrophy; however, adrenocorticotropic hormone suppression was similar for both compounds. Based on these findings, ZK 216348 should have a lower risk, e.g., for induction of diabetes mellitus. The selective GR agonists therefore represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs. Moreover, they are useful tool compounds for further investigating the mechanisms of GR-mediated effects. [ABSTRACT FROM AUTHOR]

An improved method for the solution-phase derivatization of Tyr3-Lys5(Dde)-octreotide (TOC(Dde)) and Tyr3-Lys5(Dde)-octreotate (TATE(Dde)) with the macrocyclic chelator DOTA (1,4,7,10-tetraazacyclododecane-N′,N″,N‴,N⁗-tetraacetic acid) has been developed. The fully protected parent peptides were assembled via solid-phase peptide synthesis (SPPS) using Fmoc-strategy. After cleavage from the solid support, disulfide bond formation was carried out using H2O2. Both TOC(Dde) and TATE(Dde) were successfully coupled with DOTA in the presence of NHS, EDCI and DIPEA in a water/DMF solvent system. Yields of the coupling reaction were >98% within only 2 h with no detectable formation of sideproducts. This method for the preparation of DOTATOC, DOTATATE and other DOTA-peptide conjugates is therefore a rapid and economic alternative to the currently used methods. [Copyright &y& Elsevier]

Recent papers on the role of fucosyltransferase VII (FucTVII) in leukocyte trafficking underscore the importance of this glycosyltransferase for selectin ligand synthesis, inflammation and skin homing. Furthermore, other data have shown how another transferase, FucTIV, might compensate for FucTVII functions and contribute to the generation of functional binding epitopes involved in tethering and rolling functions. [Copyright &y& Elsevier]

Because of the excellent nuclear properties of fluorine-18 and the growing interest in somatostatin receptor (sst) scintigraphy with PET, a novel carbohydrated [sup 18] F-labelled sst ligand was developed and preclinically evaluated. Synthesis of N[sup α] -(1-deoxy-D-fructosyl)-N[sup ε] -(2-[[sup 18] F]fluoropropionyl)-Lys[sup 0] -Tyr[sup 3] -octreotate ([[sup 18] F]FP-Gluc-TOCA) was completed in ~3 h (20%–30% yield). [[sup 19] F]FP-Gluc-TOCA showed no affinity to hsst1 and hsst3, moderate affinity to hsst4 (IC[sub 50] : 437±84 nM) and hsst5 (IC[sub 50] : 123±8.8 nM) and very high affinity to hsst2 (IC[sub 50] : 2.8±0.4 nM). As a result of carbohydration, lipophilicity of [[sup 18] F]FP-Gluc-TOCA was found to be low (lg P[sub OW] =–1.70±0.02). In mice, the tracer was rapidly cleared via renal excretion (kidneys: 8.69%±1.09%ID/g) and showed low uptake in liver (0.72%±0.14%ID/g) and intestine (1.88%±0.52%ID/g) and high tumour uptake (13.54%±1.47%ID/g) (all data at 1 h p.i.). Tumour to non-tumour ratios at 60 min p.i. reached 25, 19, 7, 1.6 and 56 for blood, liver, intestine, kidney and muscle, respectively. A similar biodistribution pattern was observed in pancreatic tumour-bearing rats. Tumour uptake in rats was reduced to 36% and 18% of control (30 and 60 min) by co-injection of 500 µg Tyr[sup 3] -octreotide, demonstrating sst-specific uptake. In a first [[sup 18] F]FP-Gluc-TOCA-PET study of a patient with a metastatic carcinoid in the liver the tracer showed superior pharmacokinetics, e.g. rapid urinary excretion and low uptake in liver, kidney and spleen. Multiple liver lesions (SUVs ranging from 21.4 to 38.0) and previously unknown focal uptake in the abdomen (SUV 10.0) were clearly visible. This is the first report on PET imaging using an [sup 18] F-labelled sst binding peptide; it indicates that [[sup 18] F]FP-Gluc-TOCA offers excellent imaging characteristics and allows sst imaging with... [ABSTRACT FROM AUTHOR]

Although somatostatin-based peptide receptor imaging (sst-PRI) and peptide receptor radiotherapy (sst-PRRT) of human endocrine tumours and their metastases has become a valuable method, the experience with radiohalogenated sst-directed peptides has so far been disappointing. To extend the broad spectrum of radiohalogens with suitable radionuclide properties for sst-PRI and PRRT, new strategies in ligand development are required. The major drawbacks to be overcome include fast hepatic uptake, high abdominal background activity and low tumour uptake. Recently we introduced radiolabelled glycated octreotides as a new series of sst-binding radiotracers with excellent physicochemical characteristics. In this study we compared [&sup125;I]Tyr³-octreotide ([&sup125;I]TOC, (1)), [&sup125;I]Tyr³-octreotate ([&sup125;I]TOCA, (2)) and a carbohydrated octreotide derivative, maltotriose-[&sup125;I]Tyr³-octreotate ([&sup125;I]Mtr-TOCA, (3)) to evaluate the effect of single C-terminal oxidation and simultaneous N-terminal carbohydration. The biodistribution was compared in nude mice bearing AR42J tumour xenografts. Compared with (1), activity uptake of (2) and (3) at 1 h was decreased in intestine [36% (2), 72% (3)], liver [62% (2), 79% (3)] and kidney [34% (2), 41% (3)], respectively. Blood clearance was fast for all compounds investigated. Using (1) as reference, tumour uptake of (2) and (3) was 3.8- and 4.3-fold higher at 1 h p.i. At 1 h the tumour-to-blood ratio of (3) was 28.2±7.3, and the tumour-to-muscle ratio, 147±48 . Specificity of tumour uptake was demonstrated in AR42J tumour-bearing mice by pretreatment with 0.8 mg TOC/kg 5 min prior to injection of (3). In cells transfected with sst1-sst5, the binding profile of I-Mtr-TOCA revealed a very high affinity and selectivity for sst2. In a first scintigraphic [&sup123;I]Mtr-TOCA study of a patient with a carcinoid of the small intestine with known peritoneal... [ABSTRACT FROM AUTHOR]

Faeces of immunocompromised patients are often contaminated with the chitin-containing spores of microsporidia and Candida, which exclude the use of the chitin-specific fluorescent brightener Calcofluor white M2R for the identification of microsporidian spores. We developed a combination staining of Calcofluor white M2R with modified trichrome-blue staining and subsequent methylene-blue incubation which permits discrimination between these two types of spores. As a basis for diagnosis, a difference in the fluorescence pattern (365-440 nm) is combined with a difference in the light microscopic staining pattern. Under fluorescence conditions microsporidia spores have a spotted, brilliant white Calcofluor fluorescence and can easily be identified, while Candida spores show a reddish purple colour. Under the light microscope microsporidian spores show a light red colour with nonstained vacuole spots or strips in contrast to the yeast spores with their red-brown colour. This combination technique offers a highly specific means for the diagnosis of microsporidia spores in faeces. [ABSTRACT FROM AUTHOR]

Simple Summary: Beyond its pre-eminent role in the context of tumor cell growth as well as metastasis, the C-X-C motif chemokine receptor 4 (CXCR4) is a key player in the orchestration of inflammatory responses to inflammatory stimuli. This review therefore particularly focuses on summarizing the current knowledge on non-invasive imaging of tissue infiltration with CXCR4-expressing immune cells in the context of diverse inflammatory conditions using positron emission tomography. An overview of the current clinical and preclinical approaches in this context is provided, and the recent advances in the development of dedicated, high-end CXCR4-targeted imaging tools and theranostic agents are discussed. Given its pre-eminent role in the context of tumor cell growth as well as metastasis, the C-X-C motif chemokine receptor 4 (CXCR4) has attracted a lot of interest in the field of nuclear oncology, and clinical evidence on the high potential of CXCR4-targeted theranostics is constantly accumulating. Additionally, since CXCR4 also represents a key player in the orchestration of inflammatory responses to inflammatory stimuli, based on its expression on a variety of pro- and anti-inflammatory immune cells (e.g., macrophages and T-cells), CXCR4-targeted inflammation imaging has recently gained considerable attention. Therefore, after briefly summarizing the current clinical status quo of CXCR4-targeted theranostics in cancer, this review primarily focuses on imaging of a broad spectrum of inflammatory diseases via the quantification of tissue infiltration with CXCR4-expressing immune cells. An up-to-date overview of the ongoing preclinical and clinical efforts to visualize inflammation and its resolution over time is provided, and the predictive value of the CXCR4-associated imaging signal for disease outcome is discussed. Since the sensitivity and specificity of CXCR4-targeted immune cell imaging greatly relies on the availability of suitable, tailored imaging probes, recent developments in the field of CXCR4-targeted imaging agents for various applications are also addressed. [ABSTRACT FROM AUTHOR]

The aim of this guideline is to provide recommendations for the implementation of an effective and efficient quality control (QC) programme for SPECT and PET systems in a preclinical imaging lab. These recommendations aim to strengthen the translational power of preclinical imaging results obtained using preclinical SPECT and PET. As for clinical imaging, reliability, reproducibility, and repeatability are essential when groups of animals are used in a longitudinal imaging experiment. The larger the variability of the imaging endpoint, the more animals are needed to be able to observe statistically significant differences between groups. Therefore, preclinical imaging requires quality control procedures to maintain reliability, reproducibility, and repeatability of imaging procedures, and to ensure the accuracy and precision of SPECT and PET quantification. While the Physics Committee of the European Association of Nuclear Medicine (EANM) has already published excellent procedure guidelines for Routine Quality Control Recommendations for Nuclear Medicine Instrumentation that also includes procedures for small animal PET systems, and important steps have already been made concerning preclinical quality control aspects, this new guideline provides a review and update of these previous guidelines such that guidelines are also adapted to new technological developments. [ABSTRACT FROM AUTHOR]

Presents information on a combined computation, kinetic and trapping study of the 2,5-didehydropyridine biradical. Details on experiments conducted in this research; Statistical data analyzed in this research; Results of this study.

Presents a study where p-benzyne-type biradicals abstract hydrogen unusually slowlsy. Absorption spectra; Representative total ion GC/MS trace; Product ratios in photolyses; Results of ab initio calculations.

Antibody-dependent cellular cytotoxicity (ADCC) has been implicated as an important mechanism in several highly effective monoclonal antibody-mediated cancer therapies. Bi-, tri- and multispecific natural killer (NK) cell engagers have been designed to enhance and prolong NK cell-mediated responses by targeting different activating NK cell receptors. Monotherapy with NK cell engagers or adoptive NK cell transfer has shown efficacy and can be well tolerated in certain hematological and solid malignancies. NK cell engagers have the potential to complement therapeutics that enhance adaptive T cell responses. Innate cell engagers that are precomplexed with NK cells harbor potential as novel cryopreserved off-the-shelf candidate therapeutics with chimeric antigen receptor (CAR)-NK cell-like properties, capable of effective depletion of tumor cells. Novel antibody-engineering approaches are being utilized to maximize the potential of innate immune cells via antibody-dependent cellular cytotoxicity and might provide favorable clinical outcomes across various cancer types. Bi-, tri- and multispecific antibodies have enabled the development of targeted cancer immunotherapies redirecting immune effector cells to eliminate malignantly transformed cells. These antibodies allow for simultaneous binding of surface antigens on malignant cells and activating receptors on innate immune cells, such as natural killer (NK) cells, macrophages, and neutrophils. Significant progress with such antibodies has been achieved, particularly in hematological malignancies. Nevertheless, several major challenges remain, including increasing their immunotherapeutic efficacy in a greater proportion of patients, particularly in those harboring solid tumors, and overcoming dose-limiting toxicities and immunogenicity. Here, we discuss novel antibody-engineering developments designed to maximize the potential of NK cells by NK cell engagers mediating antibody-dependent cellular cytotoxicity (ADCC), thereby expanding the armamentarium for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: CXCR3 is expressed on activated T cells and plays a crucial role in T-cell recruitment to the tumor microenvironment (TME) during cell-based and immune checkpoint inhibitor (ICI) immunotherapy. This study utilized a 64Cu-labeled NOTA-α-CXCR3 antibody to assess CXCR3 expression in the TME and validate it as a potential T cell activation biomarker in vivo. Procedures: CXCR3+ cells infiltrating MC38 tumors (B57BL/6 mice, untreated and treated with αPD-1/αCTLA-4 ICI) were quantified using fluorescence microscopy and flow cytometry. A commercial anti-mouse CXCR3 antibody (α-CXCR3) was site-specifically conjugated with 2,2,2-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) and radiolabeled with 64Cu. Saturation binding of [64Cu]Cu-NOTA-α-CXCR3 was investigated using CHO cells stably transfected with murine CXCR3. Biodistribution and PET imaging studies both at baseline and after 1 to 3 cycles of ICI, respectively, were carried out using different molar activities (10 GBq/µmol to 300 GBq/µmol) of [64Cu]Cu-NOTA-α-CXCR3. Results: Flow cytometry analysis at baseline confirmed the presence of CXCR3 + T-cells in MC38 tumors, which was significantly increased at day five after ICI (treated 33.8 ± 17.4 vs. control 8.8 ± 6.2 CD3+CXCR3+ cells/mg). These results were qualitatively and quantitatively confirmed by immunofluorescence of tumor cryoslices. In vivo PET imaging of MC38 tumor bearing mice before, during and after ICI using [64Cu]Cu-NOTA-α-CXCR3 (Kd = 3.3 nM) revealed a strong dependence of CXCR3-specificity of tracer accumulation in secondary lymphoid organs on molar activity. At 300 GBq/µmol (1.5 µg of antibody/mouse), a specific signal was observed in lymph nodes (6.33 ± 1.25 control vs. 3.95 ± 1.23%IA/g blocking) and the spleen (6.04 ± 1.02 control vs. 3.84 ± 0.79%IA/g blocking) at 48 h p.i. Spleen-to-liver ratios indicated a time dependent systemic immune response showing a steady increase from 1.08 ± 0.19 (untreated control) to 1.54 ± 0.14 (three ICI cycles). Conclusions: This study demonstrates the feasibility of in vivo imaging of CXCR3 upregulation under immunotherapy using antibodies. However, high molar activities and low antibody doses are essential for sensitive detection in lymph nodes and spleen. Detecting therapy-induced changes in CXCR3+ T cell numbers in tumors was challenging due to secondary antibody-related effects. Nonetheless, CXCR3 remains a promising target for imaging T cell activation, with anticipated improvements in sensitivity using alternative tracers with high affinities and favorable pharmacokinetics. [ABSTRACT FROM AUTHOR]

To meet the growing demand for intraoperative molecular imaging, the development of compatible imaging agents plays a crucial role. Given the unique requirements of surgical applications compared to diagnostics and therapy, maximizing translational potential necessitates distinctive imaging agent designs. For effective surgical guidance, exogenous signatures are essential and are achievable through a diverse range of imaging labels such as (radio)isotopes, fluorescent dyes, or combinations thereof. To achieve optimal in vivo utility a balanced molecular design of the tracer as a whole is required, which ensures a harmonious effect of the imaging label with the affinity and specificity (e.g., pharmacokinetics) of a pharmacophore/targeting moiety. This review outlines common design strategies and the effects of refinements in the molecular imaging agent design on the agent's pharmacological profile. This includes the optimization of affinity, pharmacokinetics (including serum binding and target mediated background), biological clearance route, the achievable signal intensity, and the effect of dosing hereon. [ABSTRACT FROM AUTHOR]

Background: The development and clinical translation of [68Ga] Pentixafor has substantially promoted the relevance of non-invasive PET imaging of CXCR4 expression in a broad spectrum of diseases, including cancer and inflammation. Its pronounced selectivity for the human receptor (hCXCR4), however, precludes the use of [68Ga] Pentixafor for imaging receptor expression and dynamics in CXCR4-related diseases in endogenous mouse models. To overcome this restriction, [125I]CPCR4.3, a structurally related pentapeptide ligand, has been evaluated as a preclinical tool for efficient in vitro and in vivo targeting of hCXCR4 and mCXCR4. Results: Compared to the reference [68Ga] Pentixafor, [125I]CPCR4.3 showed 2.4- to 11-fold increased specific binding to human cancer cell lines with different hCXCR4 expression levels (Jurkat, Daudi, HT-29, SH-5YSY, MCF-7, LNCaP) as well as strong and highly specific binding to mCXCR4 expressing cells (mCXCR4-transfected CHO cells, Eμ-myc 1080, 4 T1), which was not detectable for [68Ga]Pentixafor. This is the consequence of the equally high affinity of iodo-CPCR4 to hCXCR4 and mCXCR4 (IC50 = 5.4 ± 1.5 and 4.9 ± 1.7 nM, respectively) as opposed to [natGa] Pentixafor (hCXCR4: 42.4 ± 11.6 nM, mCXCR4: > 1000 nM). Additionally, [125I]CPCR4.3 showed enhanced tracer internalization (factor of 1.5–2 compared to the reference). In vivo biodistribution studies in immunocompetent Black Six and immunocompromised CD-1 nude mice showed predominant hepatobiliary excretion of [125I]CPCR4.3 (logP = 0.51), leading to high activity levels in liver and intestines. However, [125I]CPCR4.3 also showed high and specific accumulation in organs with endogenous mCXCR4 expression (spleen, lung, adrenals), even at low receptor expression levels. Conclusions: Due to its excellent hCXCR4 and mCXCR4 targeting efficiency, both in vitro and in vivo, [125I]CPCR4.3 represents a sensitive and reliable tool for the species-independent quantification of CXCR4 expression. Its suboptimal clearance properties will certainly restrict its use for in vivo imaging applications using 123I (for SPECT) or 124I (for PET), but due to its high and specific accumulation in mCXCR4 expressing tissues, [125I]CPCR4.3 holds promise as a powerful preclinical tool for the investigation and quantification of CXCR4 involvement and kinetics in various murine disease models via, e.g., biodistribution and autoradiography studies. [ABSTRACT FROM AUTHOR]

Background: Both in clinical routine and in preclinical research, the established standard procedure for the final purification of radiometal-labeled peptide radiopharmaceuticals is cartridge-based reversed-phase (RP) solid phase extraction (SPE). It allows the rapid and quantitative separation of the radiolabeled peptide from hydrophilic impurities and easy integration into automated synthesis procedures. However, product elution from RP cartridges necessitates the use of organic solvents and product recovery is sometimes limited. Thus, an alternative purification method based on commercially available size exclusion cartridges was investigated. Results: Since most peptide radiopharmaceuticals have a molecular weight > 1 kDa, Sephadex G10 cartridges with a molecular size cut-off of 700 Da were used for the final purification of a broad palette of 68Ga-, 64Cu- and 99mTc-labeled experimental peptide radiotracers as well as the clinically relevant ligand PSMA-617. Results (radiochemical purity (RCP, determined by ITLC), recovery from the solid support) were compared to the respective standard RP-SPE method. Generally, retention of unreacted 68Ga, 64Cu and 99mTc salts on the G10 cartridges was quantitative up to the specified elution volume (1.2 mL) for 68Ga and 99mTc and 99.6% for 64Cu. Even at increased elution volumes of 1.5-2 mL, RCPs of the eluted 68Ga- and 99mTc -radiopeptides were > 99%. For all peptides with a molecular weight ≥ 2 kDa, product recovery from the G10 cartridges was consistently > 85% upon respective adjustment of the elution volume. Product recovery was lowest for [68Ga]Ga-PSMA-617 (67%, 1.2 mL to 84%, 2 mL). The pH of the final product solution was found to be volume-dependent (1.2 mL: pH 6.3; 1.5 mL: pH 5.9; 2 mL: pH 5.5). Notably, the G10 cartridges were reused up to 20 times without compromising performance, and implementation of the method in an automated radiosynthesis procedure was successful. Conclusions: Overall, size exclusion purification yielded all peptide radiopharmaceuticals in excellent radiochemical purities (> 99%) in saline within 10–12 min. Although product recovery is marginally inferior to classical SPE purifications, this method has the advantage of completely avoiding organic solvents and representing a cost-effective, easy-to-implement purification approach for automated radiotracer synthesis. [ABSTRACT FROM AUTHOR]

Abstract Background Prostate-specific membrane antigen (PSMA)–targeted positron emission tomography (PET) can visualize metastatic lesions in recurrent prostate cancer (PC). However, reliable identification of small and/or atypically localized lesions during salvage surgery procedures is challenging. Objective To describe the technique, feasibility, and short-term outcomes of 99mTechnetium (99mTc)-based PSMA-radioguided surgery (99mTc-PSMA-RGS) for removal of recurrent PC lesions. Design, setting, and participants Thirty-one consecutive patients with evidence of recurrent PC on 68Ga-PSMA N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N′-diacetic acid (68Ga-PSMA-11) PET after radical prostatectomy undergoing 99mTc-PSMA-RGS were retrospectively analyzed. Surgical procedure Salvage surgery with intraoperative radioguidance using a gamma probe was performed after intravenous application of 99mTc-PSMA investigation and surgery (mean activity 571 MBq, mean time to surgery 19.7 h). Measurements Radioactive rating (positive vs negative) of resected tissue was compared with the findings of postoperative histopathological analysis. Best prostate-specific antigen (PSA) response without additional treatment was determined after 8–16 wk postoperatively. Biochemical recurrence- and treatment-free survival was evaluated. Results and limitations In total, 132 tissue specimens were removed, of which 58 showed metastatic involvement on histological analysis. On a specimen basis, radioactive rating yielded a sensitivity of 83.6% (confidence interval [CI]: 70.9–91.5%), a specificity of 100%, and an accuracy of 93.0% (CI: 85.5–96.7%). With 99mTc-PSMA-RGS, all lesions visualized on preoperative 68Ga-PSMA-11 PET could be removed. Moreover, 99mTc-PSMA-RGS detected additional metastases as small as 3 mm in two patients. Thirteen patients suffered from complications related to surgery (Clavien-Dindo grade 1: 12 patients; grade 3a: one patient). A PSA reduction below 0.2 ng/ml was observed in 20 patients. Thirteen patients remained biochemical recurrence free after a median follow-up of 13.8 (range: 4.6–18.3) mo. Twenty patients continued to be treatment free after a median follow-up of 12.2 (range: 5.5–18.3) mo. Conclusions As a new technique for surgical guidance, 99mTc-PSMA-RGS is feasible, and has been proved to be of high value for successful intraoperative detection and removal of metastatic lesions in PC patients scheduled for salvage surgery. Its long-term impact on outcome has to be evaluated. Patient summary In this report, we evaluated a novel technique to identify metastatic lesions intraoperatively in patients with recurrent prostate cancer to facilitate surgical removal. After intravenous injection of radioactive molecules that specifically bind to prostate cancer cells that show increased expression of the prostate-specific membrane antigen, we were able to detect and remove these metastatic lesions during surgery. Following salvage surgery, 41.9% of patients remained biochemical recurrence free (median follow-up of 13.8 mo) and 64.5% continued to be treatment free (median follow-up of 12.2 mo). Take Home Message 99mTechnetium-based prostate-specific membrane antigen–radioguided surgery as a new surgical technique is feasible, and has been proved to be of high value for successful intraoperative detection and removal of metastatic lesions in prostate cancer patients scheduled for salvage surgery. Its long-term impact on outcome has to be evaluated. [ABSTRACT FROM AUTHOR]

Background: Targeting prostate-specific membrane antigen (PSMA) has been highly successful for imaging and treatment of prostate cancer. However, heterogeneity in immunohistochemistry indicates limitations in the effect of imaging and radionuclide therapy of multifocal disease. 99mTc-PSMA-I&S is a γ-emitting probe, which can be used for intraoperative lesion detection and postsurgical autoradiography (ARG). We aimed to study its intraprostatic distribution and compared it with (immuno)-histopathology. Results: Seventeen patients who underwent RGS between 11/2018 and 01/2020 with a total of 4660 grids were included in the preliminary analysis. Marked intratumor and intra-patient heterogeneity of PSMA expression was detected, and PSMA negative foci were observed in all samples (100%). Heterogeneous intra-patient PSMA-ligand uptake was observed, and no significant correlation was present between the degree of heterogeneity of PSMA expression and PSMA-ligand uptake. Higher PSMA-ligand uptake was observed in GS ≥ 8 than GS < 8 (p < 0.001). The appearance of Gleason Pattern (GP) 4 was strongly associated with higher uptake (coefficient: 0.43, p < 0.001), while GP 5 also affected the uptake (coefficient: 0.07, p < 0.001). Conclusion: PSMA expression and PSMA-ligand uptake show marked heterogeneity. Prostate carcinoma with GP 4 showed significantly higher uptake compared with non-neoplastic prostate tissue. Our analyses extend the scope of applications of radiolabeled PSMA-ligands to ARG for identifying high-grade disease and using its signal as a noninvasive biomarker in prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: The clinical success non-invasive imaging of CXCR4 expression using [68 Ga]Ga-PentixaFor-PET warrants an expansion of the targeting concept towards conventional scintigraphy/SPECT with their lower cost and general availability. To this aim, we developed and comparatively evaluated a series of 99mTc-labeled cyclic pentapeptides based on the PentixaFor scaffold. Methods: Six mas3-conjugated CPCR4 analogs with different 4-aminobenzoic acid (Abz)-D-Ala-D-Arg-aa3 linkers (L1–L6) as well as the corresponding HYNIC- and N4-analogs of L6-CPCR4 were synthesized via standard SPPS. Competitive binding studies (IC50 and IC50inv) were carried out using Jurkat T cell lymphoma cells and [125I]FC-131 as radioligand. Internalization kinetics were investigated using hCXCR4-overexpressing Chem-1 cells. Biodistribution studies and small animal SPECT/CT imaging (1 h p.i.) were carried out using Jurkat xenograft bearing CB17/SCID mice. Based on the preclinical results, [99mTc]Tc-N4-L6-CPCR4 ([99mTc]Tc-PentixaTec) was selected for an early translation to the human setting. Five patients with hematologic malignancies underwent [99mTc]Tc-N4-L6-CPCR4 SPECT/planar imaging with individual dosimetry. Results: Of the six mas3-conjugated peptides, mas3-L6-CPCR4 (mas3-dap-r-a-Abz-CPCR4) showed the highest CXCR4 affinity (IC50 = 5.0 ± 1.3 nM). Conjugation with N4 (N4-L6-CPCR4) further improved hCXCR4 affinity to 0.6 ± 0.1 nM. [99mTc]Tc-N4-L6-CPCR4 also showed the most efficient internalization (97% of total cellular activity at 2 h) and the highest tumor accumulation (8.6 ± 1.3% iD/g, 1 h p.i.) of the compounds investigated. Therefore, [99mTc]Tc-N4-L6-CPCR4 (termed [99mTc]Tc-PentixaTec) was selected for first-in-human application. [99mTc]Tc-PentixaTec was well tolerated, exhibits a favorable biodistribution and dosimetry profile (2.1–3.4 mSv per 500 MBq) and excellent tumor/background ratios in SPECT and planar imaging. Conclusion: The successive optimization of the amino acid composition of the linker structure and the N-terminal 99mTc-labeling strategies (mas3 vs HYNIC vs N4) has provided [99mTc]Tc-PentixaTec as a novel, highly promising CXCR4-targeted SPECT agent for clinical application. With its excellent CXCR4 affinity, efficient internalization, high uptake in CXCR4-expressing tissues, suitable clearance/biodistribution characteristics, and favorable human dosimetry, it holds great potential for further clinical use. [ABSTRACT FROM AUTHOR]

A correction to the article "Twins in spirit: DOTATATE and high-affinity DOTATATE" that was published in the September 21, 2013 issue is presented.

The article focuses on the study which examines the use of metal-labelled DOTA-octreotides in somatostatin receptor imaging and therapy. The study used DOTA-iodo-Tyr3-octreotide derivatives for in vitro and preliminary positron emission tomography (PET) research. Results show the effective use of Ga-HA-DOTATATE in achieving high-quality images for peptide receptor imaging and radiotherapy (PRRT).

Background: CXCR4-targeted radioligand therapy (RLT) with [177Lu]Lu/[90Y]Y-PentixaTher has recently evolved as a promising therapeutic option for patients with advanced hematological cancers. Given their advanced disease stage, most patients scheduled for PentixaTher RLT require concomitant or bridging chemotherapy to prevent intermittent tumor progression. These (mostly combination) therapies may cause significant downregulation of tumoral CXCR4 expression, challenging the applicability of PentixaTher RLT. This study therefore aimed at investigating the influence of corticosteroids, a central component of these chemotherapies, on CXCR4 regulation in diffuse large B cell lymphoma (DLBCL). Methods: Different DLBCL cell lines (Daudi, OCI-LY1, SUDHL-4, -5-, -6 and -8) as well as the human T-cell lymphoma cell line Jurkat were incubated with Dexamethasone (Dex; 0.5 and 5 µM, respectively) and Prednisolone (Pred; 5 and 50 µM, respectively) for different time points (2 h, 24 h). Treatment-induced modulation of cellular CXCR4 surface expression was assessed via flow cytometry (FC) and compared to untreated cells. A radioligand binding assay with [125I]CPCR4.3 was performed in parallel using the same cells. To quantify potential corticosteroid treatment effects on tumoral CXCR4 expression in vivo, OCI-LY1 bearing NSG mice were injected 50 µg Dex/mouse i.p. (daily for 6 days). Then, a biodistribution study (1 h p.i.) using [68Ga]PentixaTher was performed, and tracer biodistribution in treated (n = 5) vs untreated mice (n = 5) was compared. Results: In the in vitro experiments, a strongly cell line-dependent upregulation of CXCR4 was observed for both Dex and Pred treatment, with negligible differences between the high and low dose. While in Jurkat, Daudi and SUDHL-8 cells, CXCR4 expression remained unchanged, a 1.5- to 3.5-fold increase in CXCR4 cell surface expression was observed for SUDHL-5 < SUDHL-4 /-6 < OCI-LY1 via FC compared to untreated cells. This increase in CXCR4 expression was also reflected in correspondingly enhanced [125I]CPCR4.3 accumulation in treated cells, with a linear correlation between FC and radioligand binding data. In vivo, Dex treatment led to a general increase of [68Ga]PentixaTher uptake in all organs compared to untreated animals, as a result of a higher tracer concentration in blood. However, we observed an overproportionally enhanced [68Ga]PentixaTher uptake in the OCI-LY1 tumors in treated (21.0 ± 5.5%iD/g) vs untreated (9.2 ± 2.8%iD/g) mice, resulting in higher tumor-to-background ratios in the treatment group. Conclusion: Overall, corticosteroid treatment (Dex/Pred) consistently induced an upregulation of CXCR4 expression DBLCL cells in vitro, albeit in a very cell line-dependent manner. For the cell line with the most pronounced Dex-induced CXCR4 upregulation, OCI-LY1, the in vitro findings were corroborated by an in vivo biodistribution study. This confirms that at least the corticosteroid component of stabilizing chemotherapy regimens in DLBCL patients prior to [177Lu]Lu-PentixaTher RLT does not lead to downregulation of the molecular target CXCR4 and may even have a beneficiary effect. However, further studies are needed to investigate if and to what extent the other commonly used chemotherapeutic agents affect CXCR4 expression on DLBCL to ensure the choice of an appropriate treatment regimen prior to [177Lu]Lu/[90Y]Y-PentixaTher RLT. [ABSTRACT FROM AUTHOR]

With the advent of 68 Ga-labeled prostate-specific membrane antigen- N , N ′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine- N , N ′-diacetic acid ( 68 Ga-PSMA-HBED-CC) positron emission tomography (PET) hybrid imaging in prostate cancer (PCa), even small metastatic lymph nodes (LNs) can be visualized. However, intraoperative detection of such LNs may not be easy owing to their inconspicuous morphology and/or atypical localization. The aim of our feasibility study was to evaluate PSMA-radioguided surgery for detection of metastatic LNs. One patient with primary PCa and evidence of LN metastases and four PCa patients with evidence of recurrent disease to regional LNs on 68 Ga-PSMA-HBED-CC PET hybrid imaging received an intravenous injection of an 111 In-PSMA investigation and therapy agent 24 h before surgery. Metastatic LNs were tracked intraoperatively using a gamma probe with acoustic and visual feedback. All radioactive-positive LN specimens detected in vivo were confirmed by ex vivo measurements and corresponded to PSMA-avid metastatic disease according to histopathology analysis. Intraoperative use of the gamma probe detected all PSMA-positive lesions identified on preoperative 68 Ga-PSMA-HBED-CC PET. Detection of small subcentimeter metastatic LNs was facilitated, and PSMA-radioguided surgery in two patients revealed additional lesions close to known tumor deposits that were not detected by preoperative 68 Ga-PSMA-HBED-CC PET. However, greater patient numbers and long-term follow-up data are needed to determine the future role of PSMA-radioguided surgery. [ABSTRACT FROM AUTHOR]

The document is a correction notice for an article titled "Preclinical SPECT and PET: Joint EANM and ESMI procedure guideline for implementing an efficient quality control programme" published in the European Journal of Nuclear Medicine and Molecular Imaging. The original article was published without open access but has now been made available under a Creative Commons Attribution (CC BY-NC-ND) license. The authors of the article are Christian Vanhove, Michel Koole, Pedro Fragoso Costa, Margret Schottelius, Julia Mannheim, Claudia Kuntner, Geoff Warnock, Wendy McDougald, Adriana Tavares, and Monique Bernsen. The correction notice provides links to the corrected version of the article and additional author information. [Extracted from the article]

An optimized protocol for the mild and selective Fukuyama−Mitsunobu reaction was used for mono- and di- N-alkylation on solid support. Thereby, nonfunctionalized aliphatic and aromatic residues are quickly introduced into transiently protected, primary amines of a linear peptide. N-Alkylation can also be used to implement alkyl chains carrying (protected) functionalities suited for subsequent modification. Applicability of this method is demonstrated by various N-alkylated analogues of a cyclic CXCR4 receptor antagonist originally developed by Fujii et. al. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Since the demand for 18F-fluorinated peptides for quantitative in vivo receptor imaging using PET has increased, a new chemoselective two-step 18F-labeling strategy based on hydrazone formation between an unprotected hydrazine-functionalized peptide and an 18F-labeled aldehyde was developed. Methods: First, 4-[18F]fluorobenzaldehyde ([18F]FB-CHO) was prepared from 4-formyl-N,N,N-trimethylanilinium triflate via direct no-carrier-added 18F-fluorination (dimethyl sulfoxide, 90°C, 5 min) and purified by RP-HPLC. Hydrazone formation between [18F]FB-CHO and 6-hydrazinonicotinic acid (HYNIC) and the unprotected HYNIC-functionalized peptides (HYNIC-d-Phe1)-Tyr3-Thr8-octreotide and (HYNIC-Arg1)-substance P was evaluated with respect to the dependence of radiochemical yield on pH, precursor concentration and temperature. The stability of [18F]FB-CH=N-HYNIC-Tyr3-Thr8(NH2)-octreotide in aqueous solution at various pH (4.0, 5.5 and 7.5) as well as the in vivo stability of [18F]FB-CH=N-HYNIC-Tyr3-Thr8-octreotide in mouse blood (30 min p.i.) was investigated. Results: Yields of the hydrazone formation were independent of pH between pH 0.5 and 5.5. Optimal labeling yields of 85% were obtained with a precursor concentration of 2.1 mM at 70°C for 10 min. The labeling products were stable at pH 7.5 at 37°C, while in more acidic media (pH 4.0) the product slowly decomposed to form up to 31±2% [18F]FB-CHO within 5 h. Metabolite studies showed no detectable degradation of [18F]FB-CH=N-HYNIC-Tyr3-Thr8-octreotide in mouse blood (30 min p.i.). Conclusions: In conclusion, chemoselective hydrazone formation between unprotected HYNIC-functionalized peptides and [18F]FB-CHO is a fast and straightforward radiolabeling method leading to high yields under mild acidic conditions. In addition, it represents a powerful and versatile radiolabeling strategy that is applicable to a variety of radionuclides and peptide precursors already available for 99mTc labeling. [Copyright &y& Elsevier]

Purpose: Scintigraphy with maltotriose-[123I] Tyr³-octreotate ([123I]Mtr-TOCA) is compared with [111In] DTPA-Phe¹-octreotide ([111In]OC) to assess the differences in pharmacokinetics and imaging properties as well as to estimate the therapeutic potential of the corresponding [131I]Mtr-TOCA. Methods: Six patients with somatostatin receptor (sstr)-positive tumours were assessed using a dual-head gamma camera. After injection of 137±28 MBq [123I]Mtr-TOCA, dynamic data acquisition of the upper abdomen (30 min) was performed followed by whole-body scans at 0.5 h, 1 h, 3 h and 20 h as well as by SPECT imaging (tumour) at 2 h. [111In]OC scintigraphy was performed by acquiring whole-body scans (4 h, 24 h) and SPECT (24 h). Using a region of interest (ROI) method, tissue and tumour bound activity was assessed and dosimetry performed. Results: [123I]Mtr-TOCA shows rapid tumour uptake. Up to 4 h, tumour/organ (tu/org) ratios are stable and generally higher than with [111In]OC. From 3 h to 20 h, tu/org ratios increase for spleen, remain stable for liver and decrease significantly for all other tissues. In contrast, with [111In]OC, tu/org ratios decrease slightly between 4 h and 24 h for liver, spleen and kidney and increase for all other tissues. On [123I]Mtr-TOCA scintigraphy, a total of 27 lesions are detected, whereas 33 lesions are detected on [111In]OC scintigraphy (p=0.50). Effective patient absorbed dose is 1.9±0.9 mSv per 100 MBq [123I]Mtr-TOCA. Conclusion: Compared with [111In]OC, [123I]Mtr-TOCA enables faster imaging of sstr-positive tumours with a lower radiation burden to the patient. [123I]Mtr-TOCA and [111In] OC allow for tumour imaging with almost identical contrast and diagnostic yield. As regards peptide receptor radionuclide therapy, radioiodinated Mtr-TOCA is hampered by limited intratumoural activity retention. [ABSTRACT FROM AUTHOR]

Background: Near-infrared (NIR) fluorescence imaging has been emerging as a promising strategy to overcome the high number of early esophageal adenocarcinomas missed by white light endoscopy and random biopsy collection. We performed a preclinical assessment of fluorescence imaging and endoscopy using a novel CXCR4-targeted fluorescent peptide ligand in the L2-IL1B mouse model of Barrett's esophagus. Methods: Six L2-IL1B mice with advanced stage of disease (12–16 months old) were injected with the CXCR4-targeted, Sulfo-Cy5-labeled peptide (MK007), and ex vivo wide-field imaging of the whole stomach was performed 4 h after injection. Before ex vivo imaging, fluorescence endoscopy was performed in three L2-IL1B mice (12–14 months old) by a novel imaging system with two L2-IL1B mice used as negative controls. Results: Ex vivo imaging and endoscopy in L2-IL1B mice showed that the CXCR4-targeted MK007 accumulated mostly in the dysplastic lesions with a mean target-to-background ratio > 2. The detection of the Sulfo-Cy5 signal in dysplastic lesions and its co-localization with CXCR4 stained cells by confocal microscopy further confirmed the imaging results. Conclusions: This preliminary preclinical study shows that CXCR4-targeted fluorescence endoscopy using MK007 can detect dysplastic lesions in a mouse model of Barrett's esophagus. Further investigations are needed to assess its use in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: Prostate-specific membrane antigen (PSMA) SPECT imaging in prostate cancer (PCa) could be a valuable alternative in regions where access to PSMA-PET imaging is restricted. [99mTc]Tc-PSMA-I&S is a new 99mTc-labeled PSMA-targeting SPECT agent, initially developed for radio-guided surgery. We report on the diagnostic use of [99mTc]Tc-PSMA-I&S-SPECT/CT in PCa. Results: [99mTc]Tc-PSMA-I&S-SPECT/CT was performed and evaluated in 210 outpatients with PCa at a single center. Patients were imaged for biochemical recurrence (BCR, n = 152, mean PSA 8.7 ng/ml), for primary staging of high-risk PCa (n = 12, mean PSA 393 ng/ml), and restaging in advanced recurrent PCa (n = 46, mean PSA 101.3 ng/ml). Number and location of positive lesions were determined for the different subgroups. For BCR, detection rates were calculated, defined as the proportion of scans with at least one PSMA-positive lesion. PSMA positive lesions were detected in 65.2% of all 210 patients. Tumor tissue was mainly detected in lymph nodes (59%), in the bone (42%), and in the prostate (fossa) (28%). In the subgroup of patients referred for detection of BCR the detection rate increased from 20% at a PSA level < 1 ng/ml to 82.9% and 100% at PSA levels > 4 ng/ml and > 10 ng/ml, respectively. In the subgroup of high-risk patients referred for primary staging, 42% demonstrated metastatic disease. Restaging of advanced recurrent PCa revealed detectability of PSMA positive tumor lesions in 85% of the scans. Conclusions: [99mTc]Tc-PSMA-I&S-SPECT/CT was useful in PSMA-targeted imaging of PCa at various clinical stages. At low PSA levels (< 4 ng/ml), detection rates of [99mTc]Tc-PSMA-I&S-SPECT/CT in BCR are clearly inferior to data reported for PET-imaging and should thus only be considered for lesion detection if imaging with PET is unavailable. However, at higher PSA levels (> 4 ng/ml) [99mTc]Tc-PSMA-I&S-SPECT/CT provides high detection rates in BCR. [99mTc]Tc-PSMA-I&S-SPECT/CT can also be used for primary staging and for restaging of advanced recurrent PCa. However, further studies are needed to assess the clinical value in these indications. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA)-ligand positron emission tomography (PET) allows detection of metastatic prostate cancer (PC) lesions at low prostate-specific antigen (PSA) values. To facilitate their intraoperative detection during salvage surgery, we recently introduced PSMA-targeted radioguided surgery (RGS). To describe the outcome of a large cohort of patients treated with PSMA-targeted RGS and to establish prognostic factors. A total of 121 consecutive patients with recurrent PC as defined by PSMA-ligand PET (median PSA: 1.13 ng/ml) underwent PSMA-targeted RGS. The frequency of a complete biochemical response (cBR; PSA <0.2 ng/ml) without additional treatment and the duration of biochemical recurrence-free survival (bRFS, time from PSMA-targeted RGS with PSA <0.2 ng/ml without further treatment) were evaluated and correlated with preoperatively available clinical variables. In almost all patients (120/121, 99%) metastatic tissue could be removed. A cBR was achieved in 77 patients (66%). The chance of cBR was highest in patients with both low preoperative PSA and a single lesion (38/45: 84%). Median bRFS was 6.4 mo in the whole patient cohort and 19.8 mo for patients with cBR. Significantly longer median bRFS was observed in patients with a low preoperative PSA value (p = 0.004, hazard ratio 1.48, 95% confidence interval 1.13–1.93) and with a single lesion in preoperative PSMA-ligand PET (14.0 vs 2.5 mo, p = 0.002). PSMA-targeted RGS leads to a remarkable interval of bRFS in a subset of patients. The frequency of cBR and the duration of bRFS were highest in patients with a low preoperative PSA value and a single lesion on PSMA-ligand PET. Prostate-specific membrane antigen radioguided surgery delays disease progression in selected patients with recurrent prostate cancer after radical prostatectomy. Patients with a single lesion of recurrence and a low prostate-specific antigen value had the best outcome. Prostate-specific membrane antigen (PSMA) radioguided surgery leads to a substantial prostate-specific antigen (PSA) reduction in the vast majority of patients with recurrent prostate cancer. A low PSA value and the presence of only one lesion on preoperative imaging with PSMA-ligand positron emission tomography are prognostic factors for a better outcome. [ABSTRACT FROM AUTHOR]

Background: Several radiolabeled prostate-specific membrane antigen (PSMA) inhibitors based on the lysine-urea-glutamate (KuE) motif as the pharmacophore proved to be suitable tools for PET/SPECT imaging of the PSMA expression in prostate cancer patients. PSMA I&T, a theranostic tracer developed in our group, was optimized through alteration of the peptidic structure in order to increase the affinity to PSMA and internalization in PSMA-expressing tumor cells. However, further structural modifications held promise to improve the pharmacokinetic profile.Results: Among the investigated compounds 1-9, the PSMA inhibitors 5 and 6 showed the highest PSMA affinity (lowest IC50 values) after the introduction of a naphthylalanine modification. The affinity was up to three times higher compared to the reference PSMA I&T. Extended aromatic systems such as the biphenylalanine residue in 4 impaired the interaction with the lipophilic binding pocket of PSMA, resulting in a tenfold lower affinity. The IC50 of DOTAGA-conjugated 10 was slightly increased compared to the acetylated analog; however, efficient PSMA-mediated internalization and 80% plasma protein binding of 68Ga-10 resulted in effective tumor targeting and low uptake in non-target tissues of LNCaP tumor-bearing CD-1 nu/nu mice at 1 h p.i., as determined by small-animal PET imaging and biodistribution studies. For prolonged tumor retention, the plasma protein binding was increased by insertion of 4-iodo-D-phenylalanine resulting in 97% plasma protein binding and 16.1 ± 2.5% ID/g tumor uptake of 177Lu-11 at 24 h p.i.Conclusions: Higher lipophilicity of the novel PSMA ligands 10 and 11 proved to be beneficial in terms of affinity and internalization and resulted in higher tumor uptake compared to the parent compound. Additional combination with para-iodo-phenylalanine in the spacer of ligand 11 elevated the plasma protein binding and enabled sustained tumor accumulation over 24 h, increasing the tumor uptake almost fourfold compared to 177Lu-PSMA I&T. However, high renal uptake remains a drawback and further studies are necessary to elucidate the responsible mechanism behind it. [ABSTRACT FROM AUTHOR]

The C-X-C chemokine receptor 4 (CXCR4) and its natural ligand CXCL12 are key factors in the process of cell migration, homing of hematopoietic stem cells to the bone marrow, and represent important mediators of angiogenesis and cell proliferation. The CXCR4/CXCL12 interplay can be disrupted by CXCR4 antagonists such as Plerixafor which are already in daily clinical use, i.e. for mobilization and subsequent harvesting of hematopoietic progenitor cells and stem cell transplantation. In a pathological condition, involvement in the process of metastasis and homing of cancer cells to a protective niche has been described, making CXCR4 an attractive target for imaging and treatment of malignant diseases. Recently, radiolabeled analogs of CXCR4 antagonists (e.g., [ 68 Ga]Pentixafor) have been introduced which can be used for non-invasive imaging of CXCR4 expression in animal models and humans using positron emission tomography. In addition, beta emitter-labeled antagonists (i.e., [ 177 Lu]/[ 90 Y]Pentixather) have been used in small patient cohorts for treatment of hematological neoplasms such as lymphoma, multiple myeloma and acute myeloid leukemia. This review reports on current imaging protocols for CXCR4-directed positron emission tomography in preclinical models and in humans. Furthermore, a theranostic approach using beta emitter-labeled antagonists is highlighted. Molecular imaging of the CXCR4/CXCL12 axis can contribute to further understand the process of metastatic spread and the intra-/interindividual heterogeneity of tumors. In addition, CXCR4 directed imaging allows tracking of activated, CXCR4 + immune cells. This allows for watching inflammatory processes, thus contributing to enlighten the role of the immune system in a variety of cardiovascular and neurological diseases. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the use of 111In-labelled prostate-specific membrane antigen ( PSMA)-I&T-based radioguided surgery (111In- PSMA- RGS) for salvage surgery in recurrent prostate cancer ( PCa) using comparison of intra-operative gamma probe measurements with histopathological results of dissected specimens. In addition, to determine the success of 111In- PSMA- RGS with regard to postoperative prostate-specific antigen ( PSA) responses, PCa-specific treatment-free survival rates and postoperative complication rates. Patients and Methods A total of 31 consecutive patients with localized recurrent PCa undergoing salvage surgery with PSMA-targeted radioguided surgery using a 111In-labelled PSMA ligand between April 2014 and July 2015 were retrospectively included in this study. The preoperative (interquartile range; range) median PSA level was 1.3 (0.57-2.53 ng/mL; 0.2-13.9 ng/mL). Results of ex vivo radioactivity rating (positive vs negative) of resected tissue specimens were compared with findings of postoperative histological analysis. Best PSA response without additional treatment was determined after 111In- PSMA- RGS, and salvage-surgery-related postoperative complications and PCa-specific additional treatments were recorded. Results In 30/31 patients, 111In- PSMA- RGS allowed intra-operative identification of metastatic lesions. In total, 145 surgical specimens were removed and 51 showed metastatic involvement at histological analysis. According to 111In- PSMA- RGS ex vivo measurements, 48 specimens were correctly classified as metastatic and 87 as cancer-free, four were false-negative and six were false-positive compared with histological evaluation. Follow-up information was available for 30/31 patients. PSA declines of >50% and >90% were observed in 23/30 patients and in 16/30 patients, respectively. In 18/30 patients, a PSA decline to <0.2 ng/mL was observed. In 10/30 patients further PCa-specific treatment was given after a median (range) of 125 (48-454) days post-111In- PSMA- RGS. The remaining 20 patients remained treatment-free at a median (range) follow-up of 337 (81-591) days. Of 30 patients, 10 presented with surgery-related complications (Clavien-Dindo grade 1, n = 6, Clavien-Dindo grade 3b, n = 4). Conclusion 111In- PSMA- RGS proved to be of high value for intra-operative detection of even small metastatic lesions in patients with PCa scheduled for salvage lymphadenectomy. It allows the exact localization and resection of metastatic tissue during 111In- PSMA- RGS and is therefore anticipated to have a beneficial influence on further disease progression; however, identification of suitable patients on the basis of PSMA-positron-emission tomography imaging as well as clinical variables is essential for satisfactory results to be obtained. [ABSTRACT FROM AUTHOR]

Background: Up to now, prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy mainly focused on β-emitting radionuclides. Herein, two new 213Bi-labeled agents for PSMA-targeted α therapy of prostate cancer (PCa) are reported.Methods: The biodistribution of 213Bi-labeled small-molecule inhibitor PSMA I&T and nanobody JVZ-008 was evaluated in mice bearing PSMA-positive LNCaP xenografts. DNA damage response was followed using LNCaP cells and LNCaP xenografts.Results: In vitro, 213Bi-PSMA I&T and 213Bi-JVZ-008 therapy of LNCaP cells led to increased number of DNA double-strand breaks (DSBs), detected as 53BP1 and γH2AX nuclear foci. In vivo, tumor uptake of 213Bi-PSMA I&T and 213Bi-JVZ-008 was 5.75% ± 2.70%ID/g (injected dose per gram) and 2.68% ± 0.56%ID/g, respectively, with similar tumor-to-kidney ratios. Furthermore, both agents induced in vivo DSBs in the tumors, which were detected between 1 hour and 24 hours after injection. 213Bi-PSMA I&T induced significantly more DSBs than 213Bi-JVZ-008 (p < 0.01).Conclusions: 213Bi-PSMA I&T and 213Bi-JVZ-008 showed efficient and rapid tumor targeting and produced DSBs in PSMA-expressing LNCaP cells and xenografts. These promising results require further evaluation of 213Bi-labeled agents with regard to their therapeutic efficacy and toxicity for PCa therapy. [ABSTRACT FROM AUTHOR]

Quantum tunneling is a ubiquitous phenomenon in nature and crucial for many technological applications. It allows quantum particles to reach regions in space which are energetically not accessible according to classical mechanics. In this "tunneling region," the particle density is known to decay exponentially. This behavior is universal across all energy scales from nuclear physics to chemistry and solid state systems. Although typically only a small fraction of a particle wavefunction extends into the tunneling region, we present here an extreme quantum system: a gigantic molecule consisting of two helium atoms, with an 80% probability that its two nuclei will be found in this classical forbidden region. This circumstance allows us to directly image the exponentially decaying density of a tunneling particle, which we achieved for over two orders of magnitude. Imaging a tunneling particle shows one of the few features of our world that is truly universal: the probability to find one of the constituents of bound matter far away is never zero but decreases exponentially. The results were obtained by Coulomb explosion imaging using a free electron laser and furthermore yielded He2's binding energy of 151:9 ± 13:3 neV, which is in agreement with most recent calculations. [ABSTRACT FROM AUTHOR]

Purpose: Over recent decades interest in diagnosis and treatment of neuroendocrine tumours (NET) has steadily grown. The basis for diagnosis and therapy of NET with radiolabelled somatostatin (hsst) analogues is the variable overexpression of hsst receptors (hsst1-5 receptors). We hypothesized that radiometal derivatives of DOTA-iodo-Tyr-octreotide analogues might be excellent candidates for somatostatin receptor imaging. We therefore explored the diagnostic potential of Ga-DOTA-iodo-Tyr-octreotate [Ga-DOTA,3-iodo-Tyr,Thr]octreotide (Ga-HA-DOTATATE; HA, high-affinity) compared to the established Ga-DOTA-Tyr-octreotate (Ga-DOTATATE) in vivo. Methods: The study included 23 patients with known somatostatin receptor-positive metastases from NETs, thyroid cancer or glomus tumours who were investigated with both Ga-HA-DOTATATE and Ga-DOTATATE. A patient-based and a lesion-based comparative analysis was carried out of normal tissue distribution and lesion detectability in a qualitative and a semiquantitative manner. Results: Ga-HA-DOTATATE and Ga-DOTATATE showed comparable uptake in the liver (SUV 8.9 ± 2.2 vs. 9.3 ± 2.5, n.s.), renal cortex (SUV 13.3 ± 3.9 vs. 14.5 ± 3.7, n.s.) and spleen (SUV 24.0 ± 6.7 vs. 22.9 ± 7.3, n.s.). A somewhat higher pituitary uptake was found with Ga-HA-DOTATATE (SUV 6.3 ± 1.8 vs. 5.4 ± 2.1, p < 0.05). On a lesion-by-lesion basis a total of 344 lesions were detected. Ga-HA-DOTATATE demonstrated 328 lesions (95.3 % of total lesions seen), and Ga-DOTATATE demonstrated 332 lesions (96.4 %). The mean SUV of all lesions was not significantly different between Ga-HA-DOTATATE and Ga-DOTATATE (17.8 ± 11.4 vs. 16.7 ± 10.7, n.s.). Conclusion: Our analysis demonstrated very good concordance between Ga-HA-DOTATATE and Ga-DOTATATE PET data. As the availability and use of Ga-HA-DOTATATE is not governed by patent restrictions it may be an attractive alternative to other Ga-labelled hsst analogues. [ABSTRACT FROM AUTHOR]

Theselective targeting of the αvβ3 integrin subtypewithout affecting the structurally closely related receptor α5β1is crucial for understanding the details of their biological and pathologicalfunctions and thus of great relevance for diagnostic and therapeuticapproaches in cancer treatment. Here, we present the synthesis ofhighly active RGD peptidomimetics for the αvβ3 integrinwith remarkable selectivity against α5β1. Incorporationof a methoxypyridine building block into a ligand scaffold and variationof different functional moieties led to αvβ3-antagonisticactivities in the low nanomolar or even subnanomolar range. Furthermore,docking studies were performed to give insights into the binding modesof the novel compounds. The presented library comprises powerful ligandsfor specific addressing and blocking of the αvβ3 integrinsubtype, thereby representing privileged tools for integrin-basedpersonalized medicine. [ABSTRACT FROM AUTHOR]