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Heavy alkaline earth metals offer radionuclides which are promising candidates for radiopharmaceutical applications like barium-131 for diagnosis or radium-223/-224 – with similar properties to barium – for targeted alpha-particle therapy. However, there is a lack of suitable chelation agents especially for these metal ions. A series of calix[4]crown-6 derivatives with perfluoroalkylsulfonylcarboxamide functions (RF = CF3, C2F5, i-C3F7, n-C4F9) was synthesized to serve as cage-like chelators for a strong complexation of Ba2+ and Ra2+. These functional ligands are deprotonated even at slightly acidic pH due to the intense electron withdrawing effect of the sulfonamide group. The obtained ligands were easily converted the desired barium complexes as well as into calix-crown compounds containing two sodium ions. DFT calculation methods were used to discover either the binding behavior of the metal ions with the desired ligands as well as the influence of the different donor groups from the chelating moiety of the calixarenes with respect to different pH. Radiolabeling procedures with the radionuclides barium-133 and radium-224 as [133Ba]BaCl2 and [224Ra]Ra(NO3)2 were performed to determine association constant values between 4.1 and 8.2 for the appropriate M2+ complexes using a two-phase extraction procedure. A stability test using physiological Ca2+ solution showed a minor release of approx. 1-7% of the central ions (Ba2+ respectively Ra2+) from the complexes.

Prostate specific membrane antigen (PSMA) is an excellent target for imaging and treatment of prostate carcinoma (PCa). Unfortunately, not all PCa cells express PSMA. Therefore, alternative theranostic targets are required. The membrane protein prostate stem cell antigen (PSCA) is highly overexpressed in most primary prostate carcinoma (PCa) cells and in metastatic and hor-mone refractory tumor cells. Moreover, PSCA expression positively correlates with tumor pro-gression. Therefore, it represents a potential alternative theranostic target suitable for imaging and/or radioimmunotherapy. In order to support this working hypothesis, we conjugated our previously described anti-PSCA monoclonal antibody (mAb) 7F5 with the bifunctional chelator CHX-A″-DTPA and subsequently radiolabeled it with the theranostic radionuclide 177Lu. The re-sulting radiolabeled mAb ([177Lu]Lu-CHX-A″-DTPA-7F5) was characterized both in vitro and in vivo. It showed a high radiochemical purity (>95%) and stability. The labelling did not affect its binding capability. Biodistribution studies showed a high specific tumor uptake compared to most non-targeted tissues in mice bearing PSCA-positive tumors. Accordingly, SPECT/CT images re-vealed a high tumor-to-background ratios from 16 h to 7 days after administration of [177Lu]Lu-CHX-A″-DTPA-7F5. Consequently, [177Lu]Lu-CHX-A″-DTPA-7F5 represents a promising candidate for imaging and in the future also for radioimmunotherapy.

Die Radiochemiker/Radiopharmazeuten des deutschsprachigen Raums sind im Verbund der AGRR – der „Arbeitsgemeinschaft Radiochemie und Radiopharmazie“ – innerhalb der Deutschen Gesellschaft für Nuklearmedizin organisiert. Die AGRR setzt sich vorrangig aus Kolleginnen und Kollegen der D-A-CH-Länder zusammen, sodass auf radiopharmazeutischer Seite eine Anbindung an die OGNMB und SGNM besteht. Sie pflegen dort – auch mit zahlreichen Mitgliedern aus der Industrie – während der jährlichen Arbeitstagungen einen intensiven Austausch, der über die Grenzen klassischer Vortragsveranstaltungen hinausgeht und so zu einer engen Vernetzung beiträgt. Neben klassisch-fachlichen Fragen bietet die AGRR eine Plattform zur Behandlung der vielen regulatorischen Probleme, die sowohl die pharmazeutischen als auch die Strahlenschutz-bezogenen Herausforderungen zur sicheren Versorgung der Nuklearmedizin mit anwendungsfertigen Radiopharmaka mit sich bringen.

Purpose: This prospective trial investigates the association of time to recurrence (TTR) in glioblastoma with [11C]methionine (MET) tracer uptake before postoperative radiochemotherapy (RCT) aiming to guide radiotherapy boost regions. Experimental Design: Between 2013 and 2016, 102 patients with glioblastoma were recruited. RCT was performed with concurrent and adjuvant temozolomide to a total dose of 60 Gy. Tumor residues in postresection PET and MRI were together defined as gross tumor volumes for radiotherapy treatment planning. [11C]methionine (MET)-PET/MRI was performed before RCT and at each follow-up. Results: The primary hypothesis of a longer TTR for patients without increased tracer accumulation in postoperative MET-PET was confirmed in 89 patients. With 18.9 months (95% confidence interval, 9.3–28.5 months), median TTR was significantly (P < 0.001) longer for patients without (n = 29, 32.6%) as compared with 6.3 months (3.6–8.9) for patients with MET accumulation (n = 60, 67.4%) in pre-RCT PET. Although MRI often did not detect all PET-positive regions, an unfavorable impact of residual tumor in postsurgical MRI (n = 38, 42.7%) on TTR was observed [4.6 (4.2–5.1) vs. 15.5 months (6.0–24.9), P < 0.001]. Significant multivariable predictors for TTR were MRI positivity, PET-positive volume, and O6-methylguanine DNA methyltransferase (MGMT) hypermethylation. Conclusions: Postsurgical amino acid PET has prognostic value for TTR after RCT in glioblastoma. Because of the added value of the metabolic beyond the pure structural information, it should complement MRI in radiotherapy planning if available with reasonable effort, at least in the context of maximal therapy. Furthermore, the spatial correlation of regions of recurrence with PET-positive volumes could provide a bioimaging basis for further trials, for example, testing local radiation dose escalation.

The traceless Staudinger Ligation with its two variants is a powerful biorthogonal conjugation method not only for the connection of biomolecules, but also for the introduction of fluores-cence or radiolabels under mild reaction conditions. Herein, the strategic evaluation of the traceless Staudinger Ligation for Radiolabeling 99mTc using the [Tc(CO)3] core was presented. A convenient and high-yielding three-step synthesis procedure of dipicolylamine-based phos-phanols as ligands for the mild radiolabeling was developed. The labeling was accomplished using a tricarbonyl kit and 99mTc-pertechnetate generator eluate showing 87% radiochemical conversion. The respective rhenium-based, non-radioactive reference compounds were synthe-sized using (Et4N)2[Re(CO)3Br3] as precursor. All products were analyzed by NMR, MS and ele-mental analysis. Additional XRD analyses were performed.

The adenosine A2A receptor (A2AR) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A2AR-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound. Among those, the highly affine 4-fluorobenzyl derivate (PPY1; Ki(hA2AR) = 5.3 nM) and the 2-fluorobenzyl derivate (PPY2; Ki(hA2AR) = 2.1 nM) were chosen for 18F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [18F]PPY1 and [18F]PPY2 in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [18F]PPY2 on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.

Background and purpose Systemic molecular radiotherapy utilizes internal irradiation by radionuclide-labeled tumor-targeting agents with the potential to destroy (micro-)metastases. However, doses that are applicable in solid tumors do not reach the levels nessecary for tumor control. Thus, the combination of molecular and external radiotherapy is a promising treatment strategy, as enhanced tumor doses can be delivered with and without minor overlapping toxicities. Here, we combined a 90Y-labeled anti-EGFR antibody (Cetuximab) with clinically relevant fractionated radiotherapy in a preclinical trial using head and neck squamous cell carcinoma xenograft tumors. Materials and methods To model 90Y-Cetuximab uptake for treatment schedule optimization, FaDu-bearing mice were injected with near-infrared-labeled-Cetuximab at different time points during radiotherapy with differing doses. Cetuximab uptake was longitudinally followed by in vivo-optical imaging. Tumor control probability experiments with fractionated radiotherapy (30 fx, 6 weeks, 8 dose groups/ arm) in combination with 90Y-Cetuximab were performed to test the curative potential. Results Imaging of near-infrared-labeled-Cetuximab uptake revealed that low to moderate external beam doses can enhance antibody uptake. Using the optimized schedule, combination of molecular and external radiotherapy using 90Y-Cetuximab at a dose that did not result in permanent tumor inactivation in previous experiments, led to substantially increased tumor control compared to radiotherapy alone. Conclusion Our results indicate that combination of radiolabeled therapeutics with clinically relevant fractionated radiotherapy has a remarkable potential to improve curative treatment outcome. Application of some radiation dose prior to injection may improve drug uptake and enable patient stratification and treatment personalization via a corresponding PET-tracer during therapy.

The G protein-coupled adenosine A2B receptor is suggested to be involved in various patholog-ical processes accompanied by increased levels of adenosine as found in inflammation, hypoxia, and cancer. Therefore, the adenosine A2B receptor is currently in the focus as a novel target for cancer therapy as well as for noninvasive molecular imaging via positron emission tomography (PET). Aiming at the development of a radiotracer labeled with the PET radionuclide fluorine-18 for imaging the adenosine A2B receptor in brain tumors, one of the most potent and selective an-tagonists, the xanthine derivative PSB-603, was selected as a lead compound. As initial biodis-tribution studies in mice revealed a negligible brain uptake of [3H]PSB-603 (SUV3min: 0.2), struc-tural modifications were performed to optimize the physicochemical properties regarding blood-brain barrier penetration. Two novel fluorinated derivatives bearing a 2-fluoropyridine (7) and a 4-fluoropiperidine (8) moiety have been synthesized, and their affinities for the four adenosine receptor subtypes were determined in competition binding assays. Both compounds showed high affinity towards the adenosine A2B receptor (Ki (7) = 9.97 ± 0.86 nM; Ki (8) = 12.3 ± 3.6 nM) with moderate selectivities versus the other adenosine receptor subtypes.