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Introduction: [ 18 F]SiTATE (formerly known as [ 18 F]SiFAlin-TATE) was recently introduced as a highly promising imaging agent for the diagnosis of well-differentiated neuroendocrine tumors (NET) using positron emission tomography/computed tomography (PET/CT). A high tumor uptake and excellent image quality, the straightforward labeling approach, as well as the economic and logistic advantages of 18 F- over 68 Ga-labeled compounds predestinate [ 18 F]SiTATE to become a potential new clinical reference standard. A novel state-of-the-art methodology of automated radiopharmaceutical production is required to establish [ 18 F]SiTATE in clinical routine. This work illustrates the development of a novel synthesis procedure of [ 18 F]SiTATE on an automated synthesis unit (ASU) and the clinical applicability of the tracer in human NET imaging., Methods: A new synthesis protocol was generated for the production of [ 18 F]SiTATE on the Scintomics GRP™ platform for clinical NET imaging. The synthesis was carried out according to common Good Manufacturing Practice (GMP) guidelines including all quality control measurements. To confirm utility, clinical batches (n = 3) were produced and applied to six patients diagnosed with NET., Results: [ 18 F]SiTATE was obtained in 54 ± 4% (n = 3) non-decay corrected radiochemical yield (RCY), with a radiochemical purity of 96.3 ± 0.1% and a molar activity (A m ) of 472 ± 45 GBq/μmol (n = 3). Quality control measurements always met the local release criteria. All specifications were taken or adapted from the Ph.Eur. regulations. PET/CT imaging with [ 18 F]SiTATE produced on the GRP™ module confirmed the expected high image quality. The in vivo distribution pattern and excellent tumor to non-tumor contrast observed, matched the quality of the manually prepared [ 18 F]SiTATE batches., Conclusions: The automated manufacture of [ 18 F]SiTATE was developed using the Scintomics GRP™ platform. The high quality of the radiotracer matched stringent quality control requirements adhering to common GMP guidelines, and its clinical applicability was confirmed by human PET/CT investigations., Advances in Knowledge and Implications for Patient Care: The automated process for the manufacture of [ 18 F]SiTATE described herein represents an important contribution to make [ 18 F]SiTATE routinely accessible for its use in clinical NET diagnosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Unorthodox (18)F-labeling strategies not employing the formation of a carbon-(18)F bond are seldom found in radiochemistry. Historically, the formation of a boron- or silicon-(18)F bond has been introduced very early on into the repertoire of labeling chemistries, but is without translation into any clinical radiotracer besides inorganic B[(18)F]F4(-) for brain tumor diagnosis. For many decades these labeling methodologies were forgotten and have just recently been revived by a handful of researchers thinking outside the box. When breaking with established paradigms such as the inability to obtain labeled compounds of high specific activity via isotopic exchange or performing radiofluorination in aqueous media, the research community often reacts skeptically. In 2005 and 2006, two novel labeling methodologies were introduced into radiochemistry for positron emission tomography (PET) tracer development: RBF3(-) labeling reported by Perrin et al. and the SiFA methodology by Schirrmacher, Jurkschat, and Waengler et al. which is based on isotopic exchange (IE). Both labeling methodologies have been complemented by other noncanonical strategies to introduce (18)F into biomolecules of diagnostic importance, thus profoundly enriching the landscape of (18)F radiolabeling. B- and Si-based labeling strategies finally revealed that IE is a viable alternative to established and traditional radiochemistry with the advantage of simplifying both the labeling effort as well as the necessary purification of the radiotracer. Hence IE will be the focus of this contribution over other noncanonical labeling methods. Peptides for tumor imaging especially lend themselves favorably toward one-step labeling via IE, but small molecules have been described as well, taking advantage of these new approaches, and have been used successfully for brain imaging. This Review gives an account of both radiochemistries centered on boron and silicon, describing the very beginnings of their basic research, the path that led to optimization of their chemistries, and the first encouraging preclinical results paving the way to their clinical use. This side by side approach will give the reader the opportunity to follow the development of a new basic discovery into a clinically applicable radiotracer including all the hurdles that have had to be overcome.

Recently, silicon fluoride building blocks (SiFA) have emerged as valuable and promising tools to overcome challenges in the labeling of peptides and proteins for positron emission tomography (PET). Herein, we report a fully automated synthesis of N-succinimidyl 3-(di-tert-butyl[(18)F]fluorosilyl)benzoate ([(18)F]SiFB) by a commercially available Scintomics Hot Box 3 synthesis module, to be used as a prosthetic group for peptide and protein labeling. The drying of K2.2.2./K (18)F complex was performed according to the Munich method modified by our group (avoiding azeotropic drying) using oxalic acid to neutralize the base from the (18)F(-) containing QMA eluent. This K2.2.2./K (18)F complex was then used for SiFA (18)F-(19)F isotopic exchange followed by a fast purification by a solid-phase-extraction (SPE) to afford [(18)F]SiFB with an average preparative radiochemical yield (RCY) of 24±1% (non-decay corrected (NDC)) within a synthesis time of 30 min. The [(18)F]SiFB produced by automated synthesis was then used for the (18)F-labeling of rat serum albumin (RSA) as a proof of applicability., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Over the recent years, radiopharmaceutical chemistry has experienced a wide variety of innovative pushes towards finding both novel and unconventional radiochemical methods to introduce fluorine-18 into radiotracers for positron emission tomography (PET). These "nonclassical" labeling methodologies based on silicon-, boron-, and aluminium-(18)F chemistry deviate from commonplace bonding of an [(18)F]fluorine atom ((18)F) to either an aliphatic or aromatic carbon atom. One method in particular, the silicon-fluoride-acceptor isotopic exchange (SiFA-IE) approach, invalidates a dogma in radiochemistry that has been widely accepted for many years: the inability to obtain radiopharmaceuticals of high specific activity (SA) via simple IE., Methodology: The most advantageous feature of IE labeling in general is that labeling precursor and labeled radiotracer are chemically identical, eliminating the need to separate the radiotracer from its precursor. SiFA-IE chemistry proceeds in dipolar aprotic solvents at room temperature and below, entirely avoiding the formation of radioactive side products during the IE., Scope of Review: A great plethora of different SiFA species have been reported in the literature ranging from small prosthetic groups and other compounds of low molecular weight to labeled peptides and most recently affibody molecules., Conclusions: The literature over the last years (from 2006 to 2014) shows unambiguously that SiFA-IE and other silicon-based fluoride acceptor strategies relying on (18)F(-) leaving group substitutions have the potential to become a valuable addition to radiochemistry.

The synthesis, radiolabeling and in vitro evaluation of new silicon-fluoride acceptor (SiFA) derivatized D(2)-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 D(2)-receptor affinities for all compounds in the nanomolar range (K(i(SiFA-DMFP)) = 13.6 nM, K(i(SiFA-FP)) = 33.0 nM, K(i(SiFA-DDMFP)) = 62.7 nM and K(i(SiFA-M-FP)) = 4.21 nM). The radiofluorination showed highest yields when 10 nmol of the precursors were reacted with [(18)F]fluoride/TBAHCO(3) 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.

The synthesis, radiolabeling, and initial evaluation of new silicon-fluoride acceptor (SiFA) derivatized octreotate derivatives is reported. So far, the main drawback of the SiFA technology for the synthesis of PET-radiotracers is the high lipophilicity of the resulting radiopharmaceutical. Consequently, we synthesized new SiFA-octreotate analogues derivatized with Fmoc-NH-PEG-COOH, Fmoc-Asn(Ac₃AcNH-β-Glc)-OH, and SiFA-aldehyde (SIFA-A). The substances could be labeled in high yields (38 ± 4%) and specific activities between 29 and 56 GBq/μmol in short synthesis times of less than 30 min (e.o.b.). The in vitro evaluation of the synthesized conjugates displayed a sst2 receptor affinity (IC₅₀ = 3.3 ± 0.3 nM) comparable to that of somatostatin-28. As a measure of lipophilicity of the conjugates, the log P(ow) was determined and found to be 0.96 for SiFA-Asn(AcNH-β-Glc)-PEG-Tyr³-octreotate and 1.23 for SiFA-Asn(AcNH-β-Glc)-Tyr³-octreotate, which is considerably lower than for SiFA-Tyr³-octreotate (log P(ow) = 1.59). The initial in vivo evaluation of [¹⁸F]SiFA-Asn(AcNH-β-Glc)-PEG-Tyr³-octreotate revealed a significant uptake of radiotracer in the tumor tissue of AR42J tumor-bearing nude mice of 7.7% ID/g tissue weight. These results show that the high lipophilicity of the SiFA moiety can be compensated by applying hydrophilic moieties. Using this approach, a tumor-affine SiFA-containing peptide could successfully be used for receptor imaging for the first time in this proof of concept study.

A highly efficient (18)F-labeling synthon for universal protein labeling is reported. Diverse (18)F-labeled proteins of 66-144 kDa were prepared with [(18)F]SiFA-isothiocyanate synthesized by an isotopic (19)F for (18)F exchange at the silicon atom. Overall preparative radiochemical yields were 20-40 % after 40-50 min. No bone uptake of (18)F radioactivity was detected until 90 min post-injection of (18)F-SiFA-RSA; this demonstrates the metabolic stability of the [(18)F]SiFA moiety.

Broad spectrum: Novel para-functionalized aryl-di-tert-butylfluorosilanes, p-(tBu(2)FSi)C(6)H(4)X (X=functional group), have been made available and broaden the spectrum of silicon-based (18)F acceptors (SiFAs) for potential PET applications. For example, the [(18)F]maleimido derivative 1 has been employed for the synthesis of [(18)F]1- labeled rat serum albumin (RSA), the applicability of which for PET has been verified by in vivo experiments.The syntheses of the functionalized triorganofluorosilanes tBu(2)(p-XC(6)H(4))SiF (3 a, X=SH; 4 a, X=NCS; 4 b, X=NCO; 5, X=NC(4)H(2)O(2); 7, X=COOH; 8 a, X=COONC(4)H(4)O(2); 8 b, X=COOC(6)F(5)) are reported. These compounds display potential as silicon-based fluoride acceptors (SiFAs). The molecular structures of compounds 5, 7, and 8 a have been determined by single-crystal X-ray diffraction studies. With the exception of compounds 8 a and 8 b, all of the compounds could be (18)F-labeled by isotopic exchange in good to high radiochemical yields (RCY) with good to excellent specific activities. As proof of applicability, the maleimido-functionalized SiFA derivative 5, which is specific for thiol groups, has been used for the labeling of rat serum albumin (RSA) that had been derivatized with 2-iminothiolane. The incorporation of [(18)F]5 into the derivatized RSA reached a maximum yield after 30 min at ambient temperature. After purification, the [(18)F]RSA was evaluated in a healthy rat by means of muPET and displayed an expedient in vivo stability over 180 min.