Development of a novel radiotheranostic platform with a DOTA-based trifunctional chelating agent

Abstract

We designed and synthesized a novel DOTA-based trifunctional agent containing a click ligation moiety and a pharmacological modifier for the development of a radiotheranostic platform.

Radiotheranostics Using a Novel 225Ac-Labeled Radioligand with Improved Pharmacokinetics Targeting Prostate-Specific Membrane Antigen

“…Then, TFA (1.8 mL), triisopropylsilane (TIPS) (100 μL), and H 2 O (100 μL) were added to the residue. After being stirred at room temperature for 24 h, the mixture was purified by RP-HPLC with a Cosmosil C 18 column (5C 18 PSMA-617 was synthesized according to previously described methods. 30,31 For 111 In-labeling, an [ 111 In]InCl 3 (14.8 MBq, 200 μL) solution was mixed with acetic acid−ammonium acetate buffer (0.2 M, pH 5.5, 295 μL) and preincubated at room temperature for 2 min.…”

“…On the other hand, a 1,4,7,10-tetraazacyclododecane-1,7-(diacetic acid)-4,10-diglutaric acid (DOTADG) chelator, consisting of a cyclen group linked to two acetic acids and two glutaric acids, readily generated a straight-chain DOTA-based chelate that was conjugated with two functional units. 17,18 In this study, we designed and synthesized PSMA−DA1 as a novel radiotheranostic agent (Figure 1A), in which a PSMA ligand (Glu-Lys urea), chelator (DOTADG), and ALB (N In Vitro Cell Binding. A cell-binding assay was performed to evaluate the in vitro binding of [ 111 In]In-PSMA−DA1 and [ 111 In]In-PSMA−DB to PSMA-expressing cells (Figure 2).…”

“…However, these moieties may intramolecularly interfere with each other. On the other hand, a 1,4,7,10-tetraazacyclododecane-1,7-(diacetic acid)-4,10-diglutaric acid (DOTADG) chelator, consisting of a cyclen group linked to two acetic acids and two glutaric acids, readily generated a straight-chain DOTA-based chelate that was conjugated with two functional units. , In this study, we designed and synthesized PSMA–DA1 as a novel radiotheranostic agent (Figure A), in which a PSMA ligand (Glu-Lys urea), chelator (DOTADG), and ALB ( N 6 -(4-(4-iodophenyl)­butanoyl)- l -lysine) were arranged in a straight chain, and labeled it with 111 In (γ-emitter), 90 Y (β – -emitter), or 225 Ac (α-emitter). In vitro and in vivo characterization of PSMA–DA1 and diagnostic imaging of a preclinical mouse model of human prostate cancer were conducted using 111 In-labeled PSMA–DA1, and the potential of 90 Y- or 225 Ac-labeled PSMA–DA1 as a radiotherapeutic pharmaceutical was evaluated.…”

Synthesis and Evaluation of Novel 111In-Labeled Picolinic Acid-Based Radioligands Containing an Albumin Binder for Development of a Radiotheranostic Platform

“…Radiometal-based radiotheranostics has gained much interest as a promising strategy for treating cancer. Of the various chelators used to produce radioligands for radiotheranostics, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives, which are macrocyclic chelators, are the most widely used since they can form complexes with a variety of radiometals, including γ-emitters, which are used for single-photon emission computed tomography (SPECT); β + -emitters, which are used for positron emission tomography (PET); and β – - or α-emitters, which are used for targeted radionuclide therapy (TRNT), and exhibit favorable radiolabeling rates and kinetic stability. − In particular, DOTA-based radioligands targeting prostate-specific membrane antigen (PSMA), e.g., PSMA-617 and PSMA-I&T, have been investigated as potentially useful radiotheranostic agents. ,,, In the past few years, DOTA-based PSMA-targeting radioligands labeled with α-emitting radiometals, such as 225 Ac, have shown greater therapeutic efficacy and lower toxicity in normal tissues than β – -emitter-based therapies when they were used to treat metastatic castration-resistant prostate cancer; thus, performing TRNT with α-emitters has attracted much attention as a new treatment for cancer.…”

Structure–Activity Relationships and Pharmacokinetics of 111In-Labeled Glucagon-like Peptide-1 Receptor-Targeting Exendin-4 Derivatives Conjugated with Albumin Binder Moieties

“…Recently, low-molecular-weight albumin binder (ALB) entities, e.g ., 4-(4-iodophenyl)­butyric acid and Evans blue derivatives, have been introduced into radioligands to improve the pharmacokinetics of the radioligands . ALB-conjugated radioligands, in which endogenous albumin was used as a reversible carrier for drug delivery, showed enhanced tumor accumulation and reduced renal accumulation compared with their non-ALB-conjugated counterparts. , Recently, we reported a unique radioligand design based on a 1,4,7,10-tetraazacyclododecane-1,7-(diacetic acid)-4,10-diglutaric acid (DOTADG) chelator, which enables the easy introduction of an ALB moiety. − DOTADG can be labeled with various radiometals, e.g ., 177 Lu and 225 Ac, and the resultant complexes exhibit favorable stability. , In particular, an 111 In-labeled exendin-4 derivative based on a DOTADG chelator ([ 111 In]­In-E4DA1) (Figure ), which contained a 4-(4-iodophenyl)­butyric acid derivative as an ALB moiety, showed markedly enhanced tumor uptake and reduced renal accumulation compared with its counterpart without an ALB moiety . In addition, the tumor accumulation of [ 111 In]­In-E4DA1 was over 2-fold higher than its renal accumulation at all evaluated time points, and clear tumor imaging, with only slight radioactivity within normal tissues, was achieved by performing SPECT with [ 111 In]­In-E4DA1.…”