An Automated Radiosynthesis of [68Ga]Ga-FAPI-46 for Routine Clinical Use.

[68Ga]Ga-FAPI-46 is a promising new tracer for the imaging of fibroblast activation protein (FAP) by positron emission tomography (PET). Labeled FAP inhibitors (FAPIs) have demonstrated uptake in various types of cancers, including breast, lung, prostate, pancreatic and colorectal cancer. FAPI-PET also possesses a practical advantage over FDG-PET as fasting and resting are not required. [68Ga]Ga-FAPI-46 exhibits enhanced pharmacokinetic properties, improved tumor retention, and higher contrast images than the earlier presented [68Ga]Ga-FAPI-02 and [68Ga]Ga-FAPI-04. Although a manual synthesis protocol for [68Ga]Ga-FAPI-46 was initially described, in recent years, automated methods using different commercial synthesizers have been reported. In this work, we describe the development of the automated synthesis of [68Ga]Ga-FAPI-46 using the iPHASE MultiSyn synthesizer for clinical applications. Initially, optimization of the reaction time and comparison of the performance of four different solid phase extraction (SPE) cartridges for final product purification were investigated. Then, the development and validation of the production of 0.6-1.7 GBq of [68Ga]Ga-FAPI-46 were conducted using these optimized parameters. The product was synthesized in 89.8 ± 4.8% decay corrected yield (n = 6) over 25 min. The final product met all recommended quality control specifications and was stable up to 3 h post synthesis.

Development of a high-performance liquid chromatography method for rapid radiochemical purity measurement of [18 F]PSMA-1007, a PET radiopharmaceutical for detection of prostate cancer.

Since first becoming commercially available in 2018, the PET radiopharmaceutical [18 F]PSMA-1007 has been used widely for the diagnosis and staging of prostate cancer. A pharmacopoeia monograph first became available in 2021, prescribing a radiochemical purity specification of >91%, based on analytical results from both TLC (for [18 F]fluoride impurity alone) and HPLC (for all other 18 F-impurities). Though this monograph has provided clarity for the quality control testing of [18 F]PSMA-1007, it prescribes a HPLC method using phosphate buffer mobile phase that may present a risk of precipitation of phosphate salts in the HPLC system. The method also requires specialised hardware not immediately available to all laboratories. This work describes the development of a simple, rapid reversed-phase HPLC method utilising 0.1 M ammonium formate mobile phase for the accurate assessment of both [18 F]fluoride impurity and overall radiochemical purity in a single test. This method is especially useful for assessment of product stability over time. A more accurate TLC method for [18 F]fluoride impurity is also described.

Direct in vivo comparison of [18F]PSMA-1007 with [68Ga]Ga-PSMA-11 and [18F]AlF-PSMA-11 in mice bearing PSMA-expressing xenografts.

The aim of this preclinical study was to directly compare [18F]PSMA-1007 with both [68Ga]Ga-PSMA-11 and [18F]AlF-PSMA-11 in mice bearing PSMA-positive tumor xenografts. Uptake was assessed by PET/CT at 1, 2 and 4 h post-injection, and by ex vivo measurement after 4 h. [18F]PSMA-1007 demonstrated the highest tumor uptake of the three tracers. The high uptake in bone for mice injected with [18F]AlF-PSMA-11 suggested rapid in vivo decomposition. This was confirmed by an in vitro plasma stability study.

67Ga-labeled deferoxamine derivatives for imaging bacterial infection: Preparation and screening of functionalized siderophore complexes.

INTRODUCTION: Deferoxamine (DFO) is a siderophore that bacteria use to scavenge iron and could serve as a targeting vector to image bacterial infection where current techniques have critical limitations. [67Ga]-DFO, which is a mimetic of the corresponding iron complex, is taken up by bacteria in culture, however in vivo it clears too rapidly to allow for imaging of infection. In response, we developed several new DFO derivatives to identify those that accumulate in bacteria, and at sites of infection, and that could potentially have improved pharmacokinetics. METHODS: A library of DFO derivatives was synthesized by functionalizing the terminal amine group of DFO using three different carbamate-forming reactions. Uptake of [67Ga]-DFO and the 67Ga-labeled derivatives by bacteria and the biodistribution of lead compounds were studied. RESULTS: 67Ga-labeled DFO derivatives were prepared and isolated in >90% radiochemical yield and >95% radiochemical purity. The derivatives had significant but slower uptake rates in Staphylococcus aureus than [67Ga]-DFO (6% to 60% of the control rate), with no uptake for the most lipophilic derivatives. Biodistribution studies in mice with a S. aureus infection in one thigh revealed that the ethyl carbamate derivative had an excellent infected-to-non-infected ratio (11:1), but high non-specific localization in the gall bladder, liver and small intestine. CONCLUSIONS: The work reported shows that it is possible to functionalize DFO-type siderophores and retain active uptake of the 67Ga-labeled complexes by bacteria. Novel 67Ga-labeled DFO derivatives were specifically taken up by S. aureus and selected derivatives demonstrated in vivo localization at sites of infection. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: 67Ga-labeled DFO derivatives were actively transported by bacteria using the iron-siderophore pathway, suggesting that it is possible to develop siderophore-based radiopharmaceuticals for imaging bacterial infection.

New functionalized mercaptoundecahydrododecaborate derivatives for potential application in boron neutron capture therapy: synthesis, characterization and dynamic visualization in cells.

A series of mercaptoundecahydrododecaborate (B12H11SH(2-), BSH) bearing mono- and dicarboxyalkyl derivatives was prepared, characterized, and their reactivity towards amidation and esterification in DMF was evaluated. Symmetrical alkylation of BSH was achieved by treatment with primary haloalkyl carboxylic acids in aqueous acetonitrile to produce S,S-bis(carboxyalkyl)sulfonium-undecahydro-closo-dodecaborate tetramethylammonium salts. Unsymmetrically substituted sulfonium salts were obtained through a similar treatment of cyanoethylthioether-undecahydro-closo-dodecaborate tetramethylammonium salt with haloalkyl carboxylic acid. Selective removal of the remaining cyanoethyl group upon treatment with tetramethylammonium hydroxide yielded S-carboxyalkyl-thioether-undecahydro-closo-dodecaborate ditetramethylammonium salts. N,N'-dicyclohexylcarbodiimide (DCC) activated amidation of S,S-bis(carboxyalkyl)sulfonium-undecahydro-closo-dodecaborate or S-carboxyalkyl-thioether-undecahydro-closo-dodecaborate tetramethylammonium salts with propargylamine provided the opportunity to install terminal acetylene groups for further conjugation. These compounds acted as powerful building blocks for the synthesis of a broad range of 1,4-disubstituted 1,2,3-triazole products in high yields, utilizing the Cu(I)-mediated click cycloaddition reaction. The synthesis of BSH-lipid with a two-tailed moiety was also achieved, by esterification of S,S-bis(carboxyethyl)sulfoniumundecahydro-closo-dodecaborate(1-) tetramethylammonium salt with 1,2-O-distearoyl-sn-3-glycerol, which may prove useful in the liposomal boron delivery system. The bio-compatibility of the azide-alkyne click reaction was then utilized by performing this reaction in cell culture. The distribution of BSH in HeLa cells could be visualized by treating the cells first with a BSH-alkyne compound and then with Alexa Fluor 488(®) azide dye. The BSH-dye conjugate, which did not wash out, revealed the distribution of boron in the HeLa cells. Cytotoxicity assays of these BSH derivatives revealed that the synthesized BSH-conjugated triazoles possessed low cytotoxicity in HeLa cancer cells. Of these compounds, BSH conjugated triazole 15 induced a significant increase in the level of boron accumulation in HeLa cells.

The first indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing carborane.

Indoleamine-2,3-dioxygenase-1 (IDO1) is a critical immunoregulatory enzyme responsible for the metabolism of tryptophan during inflammation and disease. Based upon a pyranonaphthoquinone framework, the first examples of indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing a carborane cage are reported. The novel closo-1,2-carboranyl-N-pyranonaphthoquinone derivatives display low µM binding affinity for the human recombinant enzyme, with IC50 values ranging from 0.78 to 1.77 µM.

High yielding synthesis of carboranes under mild reaction conditions using a homogeneous silver(I) catalyst: direct evidence of a bimetallic intermediate.

Methods used to prepare functionalized carboranes generally require heating to high temperatures, and thus limits the range of derivatives which can be prepared directly from alkynes. We show here that by using a homogeneous silver(I) catalyst it is now possible to prepare carboranes in good to excellent yield at temperatures below 40 °C, including at room temperature. The process is general and provides an important new synthetic strategy for the preparation of functionalized boron clusters.

High mitochondrial accumulation of new gadolinium(III) agents within tumour cells.

The first bifunctional Gd(III) complexes covalently bound to arylphosphonium cations and the first tumour-cell selective mitochondrial agents designed for potential application in binary cancer therapies are reported. The highest in vitro cellular uptake for any Gd complex reported to date is described, with levels exceeding 10(10) Gd atoms per tumour cell.

Remarkable cage deboronation and rearrangement of a closo-1,12-dicarbadodecaborane to form a neutral nido-7,9-dicarbaundecaborane.

Deboronation and cage rearrangement of the closo-1,12-carborane salt [1,12-(PPh2Me)2-1,12-C2B10H10]I2 occurs in refluxing methanol to give the zwitterionic nido-7,9-carborane 7,9-(PPh2Me)2-7,9-C2B9H9. Notably, deboronation and cage substitution of the isomeric closo-1,7-carborane salt [1,7-(PPh2Me)2-1,7-C2B10H10]I2 takes place in methanol to afford the salt [10-OMe-7,9-(PPh2Me)2-7,9-C2B9H9]I.

[1,2-Bis(diphenyl-phosphino)-1,2-dicarba-closo-dodeca-borane-κP,P'][7,8-bis-(di-phenyl-phosphino)-7,8-dicarba-nido-undeca-borato-κP,P']gold(I)-dichloro-methane-water (2/1/1).

The title compound, [Au(C(26)H(30)B(10)P(2))(C(26)H(30)B(9)P(2))]·0.5CH(2)Cl(2)·0.5H(2)O, contains two independent complex mol-ecules in the asymmetric unit. The gold(I) centres display a distorted tetra-hedral geometry. The complex is stablized through weak intra-molecular π-π stacking (Cg⋯Cg = 4.17 Å) and edge-to-face inter-actions (H⋯Cg = 3.21 Å). Adjacent mol-ecules inter-act through C-H⋯π (H⋯Cg = 2.88 Å) and B-H⋯π (H⋯Cg = 3.15 Å) contacts, forming a three-dimensional network, with solvent mol-ecules occupying the cavities. One of the phenyl groups was disordered over two sites with occupancy factors of 0.65 and 0.35.

Dicarba-closo-dodecaborane(12) derivatives of phosphonium salts: easy formation of nido-carborane phosphonium zwitterions.

The first examples of arylphosphonium salts containing a dicarba-closo-dodecaborane(12) (closo-carborane) are reported; in contrast to the 1,12-carborane derivative, the 1,2- and 1,7-isomers undergo a facile deboronation reaction in polar solvents to afford the corresponding nido-carborane phosphonium zwitterions.