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Here, we describe an extension of our silicon fluoride acceptor (SiFA) protocol for 18 F-labeling of peptides that addresses challenges associated with preparing a clinical-grade (Tyr 3 )-octreotate (TATE) tracer for diagnosis of neuroendocrine tumors (NETs). After several iterations of protocol optimization (e.g., finding the optimal pH at which the isotopic exchange (IE) reaction produces high radiochemical yields (RCYs)), the SiFA technology achieved clinical applicability, as showcased by radiosynthesis of [ 18 F]SiFA lin- TATE ([ 18 F]SiTATE), the first SiFA peptide used in the clinical diagnosis of NETs. The TATE peptide binds to somatostatin receptors associated with NETs. Radiolabeled TATE derivatives are routinely applied in clinical oncological PET imaging. The (SiFA) 18 F-labeling technology is based on the IE of a 19 F atom for a radioactive 18 F atom, a highly efficient labeling reaction under mild conditions. The 19 F is part of a biomolecule bearing the SiFA building block, composed of a central silicon (Si) atom, a 19 F atom connected to the Si atom, and two Si-bound tert -butyl groups. The IE proceeds through a penta-coordinate bipyramidal intermediate, followed by elimination of non-radioactive 19 F, yielding the labeled compound in high RCYs at room temperature (22 °C). The simplicity and lack of side-product formation of this approach enable a one-step, kit-like preparation of structurally complex and unprotected radiopharmaceuticals. Compounds such as peptides used for tumor imaging in nuclear medicine can be 18 F-labeled without the need for complex purification protocols. [ 18 F]SiTATE can be synthesized within 30 min in preparative RCYs of 42%, radiochemical purity of >97% and high molar activity of 60 GBq/µmol. This extension of the original silicon fluoride acceptor (SiFA) protocol for 18 F-labeling of peptides describes modifications required for the preparation of clinical-grade [ 18 F]SiFA lin -TATE for diagnosis of neuroendocrine tumors via PET imaging.

BackgroundSomatostatin-receptor (SSTR)-targeted PET/CT provides important clinical information in addition to standard imaging in meningioma patients. [18F]SiTATE is a novel, 18F-labeled SSTR-targeting peptide with superior imaging properties according to preliminary data. We provide the first [18F]SiTATE PET/CT data of a large cohort of meningioma patients.MethodsPatients with known or suspected meningioma undergoing [18F]SiTATE PET/CT were included. Uptake intensity (SUV) of meningiomas, non-meningioma lesions, and healthy organs were assessed using a 50% isocontour volume of interest (VOI) or a spherical VOI, respectively. Also, trans-osseous extension on PET/CT was assessed.ResultsA total of 107 patients with 117 [18F]SiTATE PET/CT scans were included. Overall, 231 meningioma lesions and 61 non-meningioma lesions (e.g., post-therapeutic changes) were analyzed. Physiological uptake was lowest in healthy brain tissue, followed by bone marrow, parotid, and pituitary (SUVmean 0.06 ± 0.04 vs. 1.4 ± 0.9 vs. 1.6 ± 1.0 vs. 9.8 ± 4.6; p < 0.001). Meningiomas showed significantly higher uptake than non-meningioma lesions (SUVmax 11.6 ± 10.6 vs. 4.0 ± 3.3, p < 0.001). Meningiomas showed significantly higher uptake than non-meningioma lesions (SUVmax 11.6±10.6 vs. 4.0±3.3, p<0.001). 93/231 (40.3%) meningiomas showed partial trans-osseous extension and 34/231 (14.7%) predominant intra-osseous extension. 59/231 (25.6%) meningioma lesions found on PET/CT had not been reported on previous standard imaging. ConclusionThis is the first PET/CT study using an 18F-labeled SSTR-ligand in meningioma patients: [18F]SiTATE provides extraordinary contrast in meningioma compared to healthy tissue and non-meningioma lesions, which leads to a high detection rate of so far unknown meningioma sites and osseous involvement. Having in mind the advantageous logistic features of 18F-labeled compared to 68Ga-labeled compounds (e.g., longer half-life and large-badge production), [18F]SiTATE has the potential to foster a widespread use of SSTR-targeted imaging in neuro-oncology.

PurposeRadiolabelled somatostatin analogues targeting somatostatin receptors (SSR) are well established for combined positron emission tomography/computer tomography (PET/CT) imaging of neuroendocrine tumours (NET). [18F]SiTATE has recently been introduced showing high image quality, promising clinical performance and improved logistics compared to the clinical reference standard 68Ga-DOTA-TOC. Here we present the first dosimetry and optimal scan time analysis.MethodsEight NET patients received a [18F]SiTATE-PET/CT (250 ± 66 MBq) with repeated emission scans (10, 30, 60, 120, 180 min after injection). Biodistribution in normal organs and SSR-positive tumour uptake were assessed. Dosimetry estimates for risk organs were determined using a combined linear-monoexponential model, and by applying 18F S-values and reference target masses for the ICRP89 adult male or female (OLINDA 2.0). Tumour-to-background ratios were compared quantitatively and visually between different scan times.ResultsAfter 1 h, normal organs showed similar tracer uptake with only negligible changes until 3 h post-injection. In contrast, tracer uptake by tumours increased progressively for almost all types of metastases, thus increasing tumour-to-background ratios over time. Dosimetry resulted in a total effective dose of 0.015 ± 0.004 mSv/MBq. Visual evaluation revealed no clinically relevant discrepancies between later scan times, but image quality was rated highest in 60 and 120 min images.Conclusion[18F]SiTATE-PET/CT in NET shows overall high tumour-to-background ratios from 60 to 180 min after injection and an effective dose comparable to 68Ga-labelled alternatives. For clinical use of [18F]SiTATE, the best compromise between image quality and tumour-to-background contrast is reached at 120 min, followed by 60 min after injection.

BackgroundThe positron emitting isotope fluorine-18 (18F) possesses almost ideal physicochemical properties for the development of radiotracers for diagnostic molecular imaging employing positron emission tomography (PET). 18F in its nucleophilic anionic 18F− form is usually prepared by bombarding an enriched 18O water target with protons of various energies between 5 and 20 MeV depending on the technical specifications of the cyclotron. Large thick-target yields between 5 and 14 GBq/µA can be obtained, enough to prepare large batches of radiotracers capable to serve a considerable contingent of patients (50 + per clinical batch). The overall yield of the radiotracer however depends on the efficiency of the 18F labeling chemistry. The Silicon Fluoride Acceptor chemistry (SiFA) has introduced a convenient and highly efficient way to provide clinical peptide-based 18F-radiotracers in a kit-like procedure matching the convenience of 99mTc radiopharmaceuticals.Main bodyA radiotracer’s clinical success primarily hinges on whether its synthesis can be automated. Due to its simplicity, the SiFA chemistry, which is based on isotopic exchange (18F for 19F), does not only work in a manual setup but has been proven to be automatable, yielding large batches of 18F-radiotracers of high molar activity (Am). The production of SiFA radiotracer can be centralized and the radiopharmaceutical be distributed via the “satellite” principle, where one production facility economically serves multiple clinical application sites. Clinically validated tracers such as [18F]SiTATE and [18F]Ga-rhPSMA-7/-7.3 have been synthesized in an automated synthesis unit under good manufacturing practice conditions and used in large patient cohorts. Communication of common guidelines and practices is warranted to further the dissemination of SiFA radiopharmaceuticals and to give easy access to this technology.ConclusionThis current review highlights the most recent achievements in SiFA radiopharmaceutical automation geared towards large batch production for clinical application. Best practice advice and guidance towards a facilitated implementation of the SiFA technology into new and already operating PET tracer production facilities is provided. A brief outlook spotlights the future potential of SiFA radiochemistry within the landscape of non-canonical labeling chemistries.

The incorporation of silicon fluoride acceptor (SiFA) moieties into a variety of molecules, such as peptides, proteins and biologically relevant small molecules, has improved the generation of 18F-radiopharmaceuticals for medical imaging. The efficient isotopic exchange radiofluorination process, in combination with the enhanced [18F]SiFA in vivo stability, make it a suitable strategy for fluorine-18 incorporation. This review will highlight the clinical applicability of [18F]SiFA-labeled compounds and discuss the significant radiotracers currently in clinical use.

The synthesis, radiolabeling and in vitro evaluation of new silicon-fluoride acceptor (SiFA) derivatized D2-receptor ligands is reported. The SiFA-technology simplifies the introduction of fluorine-18 into target specific biomolecules for Positron-Emission-Tomography (PET). However, one of the remaining challenges, especially for small molecules such as receptor-ligands, is the bulkiness of the SiFA-moiety. We therefore synthesized four Fallypride SiFA-conjugates derivatized either directly at the benzoic acid ring system (SiFA-DMFP, SiFA-FP, SiFA-DDMFP) or at the butyl-side chain (SiFA-M-FP) and tested their receptor affinities. We found D2-receptor affinities for all compounds in the nanomolar range (Ki(SiFA-DMFP) = 13.6 nM, Ki(SiFA-FP) = 33.0 nM, Ki(SiFA-DDMFP) = 62.7 nM and Ki(SiFA-M-FP) = 4.21 nM). The radiofluorination showed highest yields when 10 nmol of the precursors were reacted with [18F]fluoride/TBAHCO3 in acetonitrile. After a reversed phased cartridge purification the desired products could be isolated as an injectable solution after only 10 min synthesis time with radiochemical yields (RCY) of more than 40% in the case of SiFA-DMFP resulting in specific activities >41 GBq/µmol (>1,100 Ci/mmol). Furthermore, the radiolabeled products were shown to be stable in the injectable solutions, as well as in human plasma, for at least 90 min.

Silylium ions, three‐coordinated as well as donor‐stabilized, have attracted the interest of chemists for many years, have paved its way into practical application as catalysts for organic reactions, and have contributed to the understanding of fundamental chemistry problems. Since the first carbenes have been isolated and characterized, they had and still have an ongoing enormous impact on organic as well as on inorganic and organometallic chemistry. Herein, the synthesis and complete characterization of silatranyl cations as their acetonitrile‐ respectively propionitrile‐coordinated hexachlorido antimonates is reported. Upon interaction of the former with 4‐dimethylaminopyridine (DMAP) conversion to an unprecedented carbene–type complex of antimony pentachloride occurred, nicely combining silylium and carbene chemistry.

The novel 18F-labeled somatostatin receptor (SSTR)-directed radiotracer [18F]SiTATE demonstrated promising results for the imaging of various SSTR-expressing tumor types. Although thyroid carcinomas (TC) express SSTR, data on [18F]SiTATE PET/CT imaging in TC are lacking. This study explores the use of [18F]SiTATE PET/CT in a patient cohort with histologically proven TC.PURPOSEThe novel 18F-labeled somatostatin receptor (SSTR)-directed radiotracer [18F]SiTATE demonstrated promising results for the imaging of various SSTR-expressing tumor types. Although thyroid carcinomas (TC) express SSTR, data on [18F]SiTATE PET/CT imaging in TC are lacking. This study explores the use of [18F]SiTATE PET/CT in a patient cohort with histologically proven TC.As part of a prospective observational study at a single tertiary cancer center, 21 patients with TC (10 medullary (MTC) and 11 differentiated (DTC)) who underwent at least one [18F]SiTATE PET/CT were included (37 scans in total). Mean SUVmax and SUVmean of tumoral lesions, mean total-tumor-volume (TTV), and whole-body (WB)-SUVmax and WB-SUVmean on PET with their standard deviations (SDs) were determined. PET parameters were correlated to clinical parameters including tumor marker levels (thyroglobulin for DTC, calcitonin for MTC).METHODSAs part of a prospective observational study at a single tertiary cancer center, 21 patients with TC (10 medullary (MTC) and 11 differentiated (DTC)) who underwent at least one [18F]SiTATE PET/CT were included (37 scans in total). Mean SUVmax and SUVmean of tumoral lesions, mean total-tumor-volume (TTV), and whole-body (WB)-SUVmax and WB-SUVmean on PET with their standard deviations (SDs) were determined. PET parameters were correlated to clinical parameters including tumor marker levels (thyroglobulin for DTC, calcitonin for MTC).89 lesions were included in the analysis. Metastases were localized in the bone, lymph nodes, lung, soft tissue, and thyroid bed. Osseous (31 lesions; SUVmax 8.6 ± 8.0; SUVmean 5.8 ± 5.4) and nodal (37 lesions; SUVmax 8.7 ± 7.8; SUVmean 5.7 ± 5.4) metastases showed the highest uptake. The MTC disease burden on PET significantly correlated with the calcitonin tumor marker level (e.g., TTV: r = 0.771, r2 = 0.594, p = 0.002). For DTC, no such correlation was present.RESULTS89 lesions were included in the analysis. Metastases were localized in the bone, lymph nodes, lung, soft tissue, and thyroid bed. Osseous (31 lesions; SUVmax 8.6 ± 8.0; SUVmean 5.8 ± 5.4) and nodal (37 lesions; SUVmax 8.7 ± 7.8; SUVmean 5.7 ± 5.4) metastases showed the highest uptake. The MTC disease burden on PET significantly correlated with the calcitonin tumor marker level (e.g., TTV: r = 0.771, r2 = 0.594, p = 0.002). For DTC, no such correlation was present.Our data demonstrate high feasibility of [18F]SiTATE PET/CT in a small cohort of patients with MTC and DTC. The use of [18F]SiTATE may overcome logistical disadvantages of 68Ga-based tracers and facilitate SSTR-targeted PET/CT imaging of thyroid carcinoma.CONCLUSIONOur data demonstrate high feasibility of [18F]SiTATE PET/CT in a small cohort of patients with MTC and DTC. The use of [18F]SiTATE may overcome logistical disadvantages of 68Ga-based tracers and facilitate SSTR-targeted PET/CT imaging of thyroid carcinoma.

Silylium ions, three‐coordinated as well as donor‐stabilized, have attracted the interest of chemists for many years, have paved its way into practical application as catalysts for organic reactions, and have contributed to the understanding of fundamental chemistry problems. Since the first carbenes have been isolated and characterized, they had and still have an ongoing enormous impact on organic as well as on inorganic and organometallic chemistry. Herein, the synthesis and complete characterization of silatranyl cations as their acetonitrile‐ respectively propionitrile‐coordinated hexachlorido antimonates is reported. Upon interaction of the former with 4‐dimethylaminopyridine (DMAP) conversion to an unprecedented carbene–type complex of antimony pentachloride occurred, nicely combining silylium and carbene chemistry.