In vivo stable At-labeled prostate-specific membrane antigen-targeted tracer using a neopentyl glycol structure.

Background: Prostate cancer is a common cancer among men worldwide that has a very poor prognosis, especially when it progresses to metastatic castration-resistant prostate cancer (mCRPC). Therefore, novel therapeutic agents for mCRPC are urgently required. Because prostate-specific membrane antigen (PSMA) is overexpressed in mCRPC, targeted alpha therapy (TAT) for PSMA is a promising treatment for mCRPC.

Development of a Neopentyl At-Labeled Activated Ester Providing In Vivo Stable At-Labeled Antibodies for Targeted Alpha Therapy.

In this study we developed a neopentyl At-labeled activated ester that incorporates a triazole spacer and applied it to the synthesis of an At-labeled cetuximab. The activated ester was synthesized via the nucleophilic At-astatination of a neopentyl sulfonate carrying two long alkyl chains that serve as a lipid tag, which was followed by the hydrolysis of an acetal. Additionally, we developed a novel Resin-Assisted Purification and Deprotection (RAPD) protocol involving a solid-phase extraction of the protected At-labeled compound from the mixture of the labeling reaction, hydrolysis of the acetal on the resin, and finally an elution of the At-labeled activator from the resin.

Neopentyl glycol-based radiohalogen-labeled amino acid derivatives for cancer radiotheranostics.

Background: L-type amino acid transporter 1 (LAT1) is overexpressed in various cancers; therefore, radiohalogen-labeled amino acid derivatives targeting LAT1 have emerged as promising candidates for cancer radiotheranostics. However, At-labeled amino acid derivatives exhibit instability against deastatination in vivo, making it challenging to use At for radiotherapy. In this study, radiohalogen-labeled amino acid derivatives with high dehalogenation stability were developed.

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

The high stability of 2,2-dihydroxymethyl-3-[F]fluoropropyl-2-nitroimidazole ([F]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 I-labeled compounds remained stable against nucleophilic substitution, only a I-labeled neopentyl glycol was stable against cytochrome P450 (CYP)-mediated metabolism and showed high stability against deiodination.

Copper-64-Labeled Antibody Fragments for Immuno-PET/Radioimmunotherapy with Low Renal Radioactivity Levels and Amplified Tumor-Kidney Ratios.

Copper-64 (Cu)-labeled antibody fragments such as Fab are useful for molecular imaging (immuno-PET) and radioimmunotherapy. However, these fragments cause high and persistent localization of radioactivity in the kidneys after injection. To solve this problem, this study assessed the applicability of a molecular design to Cu, which reduces renal radioactivity levels by liberating a urinary excretory radiometabolite from antibody fragments at the renal brush border membrane (BBM).