Imaging of β-amyloid (Aβ) plaques in the brain may facilitate the diagnosis of cerebral β-amyloidosis, risk prediction of Alzheimer’s disease (AD), and effectiveness of anti-amyloid therapies. The purpose of this study was to evaluate novel 123I-labeled pyridyl benzofuran derivatives as SPECT probes for Aβ imaging. The formation of a pyridyl benzofuran backbone was accomplished by Suzuki coupling. [123I/125I]-labeled pyridyl benzofuran derivatives were readily prepared by an iododestannylation reaction. In vitro Aβ binding assays were carried out using Aβ(1–42) aggregates and postmortem human brain sections. Biodistribution experiments were conducted in normal mice at 2, 10, 30, and 60 min postinjection. Aβ labeling in vivo was evaluated by small-animal SPECT/CT in Tg2576 transgenic mice injected with [123I]8. Ex vivo autoradiography of the brain sections was performed after SPECT/CT. Iodinated pyridyl benzofuran derivatives showed excellent affinity for Aβ(1–42) aggregates (2.4 to 10.3 nM) and intensely labeled Aβ plaques in autoradiographs of postmortem AD brain sections. In biodistribution experiments using normal mice, all these derivatives displayed high initial uptake (4.03–5.49% ID/g at 10 min). [125I]8 displayed the quickest clearance from the brain (1.30% ID/g at 60 min). SPECT/CT with [123I]8 revealed higher uptake of radioactivity in the Tg2576 mouse brain than the wild-type mouse brain. Ex vivo autoradiography showed in vivo binding of [123I]8 to Aβ plaques in the Tg2576 mouse brain. These combined results warrant further investigation of [123I]8 as a SPECT imaging agent for visualizing Aβ plaques in the AD brain.

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.

Hypoxic cells dynamically translocate during tumor growth and after radiotherapy. The most desirable direction for therapy targeting hypoxic cells is combining imaging and therapy (theranostics), which may help realize personalized medicine. Here, we conducted cancer radiotheranostics targeting carbonic anhydrase-IX (CA-IX), which is overexpressed in many kinds of hypoxic cancer cells, using low-molecular-weight 111In and 90Y complexes with a bivalent ureidosulfonamide scaffold as the CA-IX-binding moiety ([111In/90Y]US2).Methods: The targeting ability of [111In]US2 was evaluated by in vivo biodistribution study in CA-IX high-expressing (HT-29) tumor-bearing mice. In vivo imaging of HT-29 tumors was carried out using single photon emission computed tomography (SPECT). [90Y]US2 was administered to HT-29 tumor-bearing mice to evaluate cancer therapeutic effects.Results: [111In]US2 highly and selectively accumulated within HT-29 tumors (4.57% injected dose/g tumor at 1 h postinjection), was rapidly cleared from the blood pool and muscle after 4 h based on a biodistribution study, and visualized HT-29 tumor xenografts in mice at 4 h postinjection with SPECT. Radionuclide-based therapy with [90Y]US2 significantly delayed HT-29 tumor growth compared with that of untreated mice (P = 0.02 on day 28, Student's t-test), without any critical hematological toxicity due to its rapid pharmacokinetics.Conclusion: These results indicate that cancer radiotheranostics with [111In/90Y]US2 provides a novel strategy of theranostics for cancer hypoxia.

Deposition of amyloid aggregates has been regarded as an early stage of amyloidosis progression. An imaging probe that can image amyloid aggregates enables the early diagnosis of amyloidosis and contributes to the development of new medical therapies. High binding affinity for amyloid aggregates is essential to develop a useful molecular imaging probe. This article describes a new strategy to enhance the binding affinity of imaging agents targeting amyloid aggregates. We designed and synthesized novel (99m)Tc-hydroxamamide ((99m)Tc-Ham) complexes with a bivalent amyloid ligand and evaluated their binding affinity for amyloid aggregates by using β-amyloid peptide (Aβ(1-42)) aggregates as a model. In vitro inhibition assay indicated that bivalent (99m)Tc-Ham complexes had much higher binding affinity for amyloid aggregates than monovalent complexes. In vitro autoradiography using Tg2576 mice showed the specific binding of bivalent (99m)Tc-Ham complexes to Aβ plaques in the mouse brain, as reflected in the results of the inhibition assay. The preliminary results suggest that a new molecular design based on bivalent (99m)Tc-Ham complexes may be reasonable to develop an imaging probe targeting amyloid aggregates.

225Ac-based radiotheranostics targeting prostate-specific membrane antigen (PSMA) has induced impressive responses in patients with metastatic castration-resistant prostate cancer. To enhance the therapeutic effects of radioligands labeled with 225Ac (half-life: 10 days), a radioligand that shows longer tumor retention would be useful. Here, we designed and synthesized a straight-chain PSMA-targeting radioligand, PSMA–DA1, which includes an (iodophenyl)­butyric acid derivative as an albumin binder (ALB). We performed preclinical evaluations of PSMA–DA1 as a tool for PSMA-targeting radiotheranostics using 111In, 90Y, and 225Ac. [111In]­In-PSMA–DA1 demonstrated significantly greater tumor uptake and retention than a corresponding non-ALB-conjugated compound. In mice, single-photon emission computed tomography performed with [111In]­In-PSMA–DA1 produced clear tumor images, and the administration of [90Y]­Y-PSMA–DA1 or [225Ac]­Ac-PSMA–DA1 inhibited tumor growth. [225Ac]­Ac-PSMA–DA1 had antitumor effects in mice at a lower radioactivity level than [225Ac]­Ac-PSMA-617, which has been reported to be clinically useful. These results indicate that PSMA–DA1 may be a useful PSMA-targeting radiotheranostic agent.