Modulation of the Pharmacokinetics of a Radioligand Targeting Carbonic Anhydrase-IX with Albumin-Binding Moieties

Abstract

The expression of carbonic anhydrase-IX (CA-IX) in tumors can lead to a poor prognosis; thus, CA-IX has attracted much attention as a target molecule for cancer diagnosis and treatment. An 111 In-labeled imidazothiadiazole sulfonamide (IS) derivative, [ 111 In]In-DO3A-IS1, exhibited marked tumor accumulation but also marked renal accumulation, raising concerns about it producing a low signal/background ratio and a high radiation burden on the kidneys. In this study, four 111 In-labeled IS derivatives, IS-[ 111 In]In-DO2A-ALB1−4, which contained four different kinds of albumin binder (ALB) moieties, were designed and synthesized with the aim of improving the pharmacokinetics of [ 111 In]In-DO3A-IS1. Their utility for imaging tumors that strongly express CA-IX was evaluated in mice. An in vitro binding assay of cells that strongly expressed CA-IX (HT-29 cells) was performed using acetazolamide as a competitor against CA-IX, and IS-[ 111 In]In-DO2A-ALB1−4 did not exhibit reduced binding to HT-29 cells compared with [ 111 In]In-DO3A-IS1. In contrast, IS-[ 111 In]In-DO2A-ALB1−4 showed a greater ability to bind to human serum albumin than [ 111 In]In-DO3A-IS1 in vitro. In an in vivo biodistribution study, the introduction of an ALB moiety into the 111 Inlabeled IS derivative markedly decreased renal accumulation and increased HT-29 tumor accumulation and blood retention. The pharmacokinetics of the IS derivatives varied depending on the substituted group within the ALB moiety. Single-photon emission computed tomography imaging with IS-[ 111 In]In-DO2A-ALB1, which showed the highest tumor/kidney ratio in the biodistribution study, facilitated clear HT-29 tumor imaging, and no strong signals were observed in the normal organs. These results indicate that IS-[ 111 In]In-DO2A-ALB1 may be an effective CA-IX imaging probe and that the introduction of ALB moieties may improve the pharmacokinetics of CA-IX ligands.

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

“…24 On the other hand, we previously described a straight-chain ALB-conjugated radioligand (IS-[ 111 In]In-DO2A-ALB1) targeting carbonic anhydrase-IX (CA-IX), in which an ALB moiety was conjugated to a carboxylic acid group on the opposite side of a chelator (DO2A) from a CA-IX ligand. 20 The CA-IX ligand and the ALB moiety could not approach each other intramolecularly; therefore, they were able to bind to CA-IX and albumin, respectively, without interfering with each other. However, the chelator DO2A consists of a cyclen group linked to four acetic acids, in which two carboxylic acid groups are used for conjugation with a targeting ligand and ALB.…”

“…20 The introduction of N 6 -(4-(4-iodophenyl)butanoyl)-L-lysine into a DOTADG-based PSMA radioligand significantly enhanced the binding to plasma proteins to the level exhibited by our previously reported probes. 20 [ 111 In]In-PSMA−DB, which does not possess an ALB moiety, also bound to plasma proteins, which is consistent with the fact that a non-ALB-conjugated CA-IX probe exhibited low levels of protein binding.…”

“…We previously studied the structure−activity relationships and pharmacokinetics of ALB using CA-IX probes, which showed that the introduction of N 6 -(4-(4-iodophenyl)butanoyl)-L-lysine as an ALB moiety most strongly enhanced the blood retention of the probes. 20 The introduction of N 6 -(4-(4-iodophenyl)butanoyl)-L-lysine into a DOTADG-based PSMA radioligand significantly enhanced the binding to plasma proteins to the level exhibited by our previously reported probes. 20 [ 111 In]In-PSMA−DB, which does not possess an ALB moiety, also bound to plasma proteins, which is consistent with the fact that a non-ALB-conjugated CA-IX probe exhibited low levels of protein binding.…”

“…The binding of [ 111 In]In-PSMA−DA1 and [ 111 In]In-PSMA−DB to plasma proteins was evaluated using gel filtration chromatography, according to our previously described method (Figure S2). 20 After being incubated in phosphate-buffered saline (PBS), neither (2.69% ID/g at 24 h post injection and 0.61% ID/g at 1 h post injection, respectively; Figure 3D and Tables S4 and S5).…”

New Developments in Carbonic Anhydrase IX-Targeted Fluorescence and Nuclear Imaging Agents

“…The tumors were clearly visualized at 4 h, and the best imaging contrast was found at 24 h PI However, high accumulation in the kidney was observed (65.1–115% ID/g at 1–24 h PI). In order to reduce the uptake in non-target organs, they introduced an albumin binder (ALB) into 18 to generate [ 111 In]In-DO2A-ALB1 ( 19 ) [ 51 ]. ALB moieties, such as 4-( p -iodophenyl)-butyric acid, exhibit reversible binding to albumin in the blood with a micromolar affinity, which prolongs the circulation time of the tracer, thereby enhancing its tumor uptake.…”