Synthesis and Preclinical Evaluation of [18F]SiFA-PSMA Inhibitors in a Prostate Cancer Model.

Positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) with gallium-68 (68Ga) and fluorine-18 (18F) radiotracers has aroused tremendous interest over the past few years. The use of organosilicon-[18F]fluoride acceptors (SiFA) conjugated to urea-based peptidomimetic PSMA inhibitors provides a "kit-like" multidose synthesis technology. Nine novel 18F-labeled SiFA-bearing PSMA inhibitors with different linker moieties were synthesized and analyzed for their in vitro binding against [125I]I-TAAG-PSMA in LNCaP cells. IC50 values ranged from 58-570 nM. Among all compounds, [18F]SiFA-Asp2-PEG3-PSMA (IC50 = 125 nM) showed the highest tumor uptake in LNCaP tumors (SUV60min 0.73). A substantial increase in molar activity (Am) (from 7.5 ± 0.5 to 86 ± 3 GBq/µmol) led to a significant increase in LNCaP tumor uptake (SUV60min 1.18; Δ 0.45 corresponding to +62%). In vivo blocking with DCFPyL resulted in -32% uptake after 60 min. The SiFA-isotopic exchange chemistry offers a method that is readily adaptable for a "kit-type" labeling procedure and clinical translation.

PET Imaging of Meningioma Using the Novel SSTR-Targeting Peptide 18F-SiTATE.

ABSTRACT: PET using 68Ga-labeled somatostatin receptor (SSTR) ligands adds significant information in meningioma patients. 18F-SiTATE is a novel, 18F-labeled SSTR-targeting peptide with remarkable imaging properties. Here, we present a 72-year-old woman with falx meningioma and transosseous extension. 18F-SiTATE PET/CT was performed 12 months after the previous 68Ga-DOTATOC PET/CT with comparable quantitative uptake and very good spatial resolution. So far, the widespread use of SSTR ligands for NET and meningioma imaging is hampered by cost-intensive 68Ge/68Ga generators, low activity amounts, lower spatial resolution, and short half-life. 18F-SiTATE might foster widespread use of SSTR ligands, overcoming the shortcomings of 68Ga-labeled ligands.

¹8F-labeled silicon-based fluoride acceptors: potential opportunities for novel positron emitting radiopharmaceuticals.

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.

Rapid (18)F-labeling and loading of PEGylated gold nanoparticles for in vivo applications.

Water-soluble 3 nm maleimide-terminated PEGylated gold nanoparticles (maleimide-AuNP) were synthesized in both partially hydrolyzed and nonhydrolyzed forms. Both of these maleimide-AuNPs, when reacted with the silicon-fluorine prosthetic group [(18)F]SiFA-SH, resulted in radiolabeled AuNPs. These NPs were readily purified with high radiochemical yields (RCY) of 60-80% via size exclusion chromatography. Preliminary small animal positron emission tomography (PET) measurements in healthy rats gives information about the pathway of excretion and the stability of the radioactive label in vivo. The partially hydrolyzed [(18)F]SiFA-maleimide-AuNPs shows uptake in the brain region of interest (ROI) (> 0.13%ID/g) which was confirmed by ex vivo examination of the thoroughly perfused rat brain. The multiple maleimide end groups on the AuNP surface also allows for the simultaneous incorporation of [(18)F]SiFA-SH and a bioactive peptide (cysteine-modified octreotate, cys-TATE, which can bind to somatostatin receptor subtypes 2 and 5) in a proof-of-concept study. The well-defined Michael addition reaction between various thiol containing molecules and the multifunctionalized maleimide-AuNPs thus offers an opportunity to develop a new bioconjugation platform for new diagnostics as well as therapeutics.

Oxalic acid supported Si-18F-radiofluorination: one-step radiosynthesis of N-succinimidyl 3-(di-tert-butyl[18F]fluorosilyl)benzoate ([18F]SiFB) for protein labeling.

N-Succinimidyl 3-(di-tert-butyl[(18)F]fluorosilyl)benzoate ([(18)F]SiFB), a novel synthon for one-step labeling of proteins, was synthesized via a simple (18)F-(19)F isotopic exchange. A new labeling technique that circumvents the cleavage of the highly reactive active ester moiety under regular basic (18)F-labeling conditions was established. In order to synthesize high radioactivity amounts of [(18)F]SiFB, it was crucial to partially neutralize the potassium oxalate/hydroxide that was used to elute (18)F(-) from the QMA cartridge with oxalic acid to prevent decomposition of the active ester moiety. Purification of [(18)F]SiFB was performed by simple solid-phase extraction, which avoided time-consuming HPLC and yielded high specific activities of at least 525 Ci/mmol and radiochemical yields of 40-56%. In addition to conventional azeotropic drying of (18)F(-) in the presence of [K(+)⊂2.2.2.]C(2)O(4), a strong anion-exchange (SAX) cartridge was used to prepare anhydrous (18)F(-) for nucleophilic radio-fluorination omitting the vacuum assisted drying of (18)F(-). Using a lyophilized mixture of [K(+)⊂2.2.2.]OH resolubilized in acetonitrile, the (18)F(-) was eluted from the SAX cartridge and used directly for the [(18)F]SiFB synthesis. [(18)F]SiFB was applied to the labeling of various proteins in likeness to the most commonly used labeling synthon in protein labeling, N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). Rat serum albumin (RSA), apo-transferrin, a ß-cell-specific single chain antibody, and erythropoietin were successfully labeled with [(18)F]SiFB in good radiochemical yields between 19% and 36%. [(18)F]SiFB- and [(18)F]SFB-derivatized RSA were directly compared as blood pool imaging agents in healthy rats using small animal positron emission tomography. Both compounds demonstrated identical biodistributions in healthy rats, accurately visualizing the blood pool with PET.