1-(N,N-Dialkylcarbamoyl)-1,1-difluoromethanesulfonyl ester as a stable and effective precursor for a neopentyl labeling group with astatine-211.

Radiohalogens with a short half-life are useful radioisotopes for radiotheranostics. Astatine-211 is an α-emitting radiohalogen and is expected to be applicable to targeted α therapy. A neopentyl labeling group is an effective hydrophilic labeling unit for various radiohalogens, which includes 211At. In this study, a 1-(N,N-dialkylcarbamoyl)-1,1-difluoromethanesulfonyl (CDf) ester was developed as a stable precursor for labeling with 211At, 77Br and 125I through a neopentyl labeling group. The CDf ester remained stable in an acetonitrile solution at room temperature and enabled the successful syntheses of 211At-labeled compounds in a highly radiochemical conversion in the presence of K2CO3. 77Br- and 125I-labeled compounds can be prepared from the CDf ester without a base. The utility of the CDf ester was demonstrated in the synthesis of a benzylguanidine with a neopentyl 211At-labeling group. The developed method afforded a 32% radiochemical yield of 211At-labeled benzylguanidine. However, a partial deastatination was observed under acidic conditions during the removal of an N-Boc protecting group. Deprotecting these groups under milder acidic conditions may improve the radiochemical yield. In conclusion, the CDf ester facilitates the syntheses of 211At, 125I and 77Br-labeled compounds that use a neopentyl labeling group for radiotheranostic applications. Further optimization of protecting groups and reaction conditions should enhance the total radiochemical yield of the 211At-labeled compounds.

Neopentyl Glycol as a Scaffold to Provide Radiohalogenated Theranostic Pairs of High In Vivo Stability.

The high in vivo stability of 2,2-dihydroxymethyl-3-[18F]fluoropropyl-2-nitroimidazole ([18F]DiFA) prompted us to evaluate neopentyl as a scaffold to prepare a radiotheranostic system with radioiodine and astatine. Three DiFA analogues with one, two, or without a hydroxyl group were synthesized. While all 125I-labeled compounds remained stable against nucleophilic substitution, only a 125I-labeled neopentyl glycol was stable against cytochrome P450 (CYP)-mediated metabolism and showed high stability against in vivo deiodination. 211At-labeled neopentyl glycol also remained stable against both nucleophilic substitution and CYP-mediated metabolism. 211At-labeled neopentyl glycol showed the biodistribution profiles similar to those of its radioiodinated counterpart in contrast to the 125I/211At-labeled benzoate pair. The urine analyses confirmed that 211At-labeled neopentyl glycol was excreted in the urine as a glucuronide conjugate with the absence of free [211At]At-. These findings indicate that neopentyl glycol would constitute a promising scaffold to prepare a radiotheranostic system with radioiodine and 211At.

Effects of 18F-fluorinated neopentyl glycol side-chain on the biological characteristics of stilbene amyloid-ß PET ligands.

INTRODUCTION: The 2,2-dihydroxymethyl-1-[18F]fluoropropane group, also called 18F-labelled neopentyl glycol side-chain, is a novel 18F-labelling group for positron emission tomography (PET) imaging agents. The aim of using this group is to develop simple purification with solid-phase extraction without high-performance liquid chromatography. However, the effects of the neopentyl 18F-labelling group on the characteristics of brain imaging agents are unknown. Here, we added this side-chain to compounds with an aminostilbene structure to evaluate their effects on the biological properties of aminostilbene as an amyloid-ß (Aß) radioligand. METHODS: Biodistributions of four novel 18F-labelled stilbene compounds with different lengths of polyethylene glycol (PEG) linkers, called [18F]Cpd-0, -1, -2, and -4, (PEG = 0, 1, 2, and 4), and [18F]AV-1 in normal mice were evaluated. Metabolite analysis of [18F]Cpd-0 and -1 was performed with mouse plasma and brain. A competitive binding assay of [18F]AV-1 binding to Aß1-42 fibrils was performed to determine the binding properties of the compounds. RESULTS: [18F]Cpd-0, -1, and -2 demonstrated moderate initial brain uptake in mice (3.1-4.2% injected dose/g at 2 min post-injection) followed by fast clearance, and in vivo defluorination of these compounds was negligible. [18F]Cpd-4 exhibited low brain uptake and high bone uptake. Compared with [18F]Cpd-1, the percentage of [18F]Cpd-0 in mouse brain was high at 10 min post-injection. A competitive binding assay revealed partial interference effects by the neopentyl glycol side-chain on binding of stilbene compounds to Aß1-42 fibrils. CONCLUSIONS: Aminostilbene compounds with two or fewer PEG linkers containing an 18F-labelled neopentyl glycol side-chain demonstrated preferable pharmacokinetic properties as a brain imaging radioligand in normal mice. These side-chains can be used as an alternative labelling group for imaging agents targeting the brain.