Advances in Drug Design of Radiometal-Based Imaging Agents for Bone Disorders

Nuclear medicine bone imaging has been the optimum diagnosis for the detection of bone disorders because the lesion could be detectable before the appearance of symptomatic and radiographic changes. Over the past three decades, 99mTc-MDP and 99mTc-HMDP have been used as bone scintigraphic agents because of their superior biodistribution characteristics, although they are far from optimal from a chemical and pharmaceutical point of view. Recently, a more logical drug design has been proposed as a concept of bifunctional radiopharmaceuticals in which the carrier molecules (bisphosphonates) and radiometal chelating groups are separated within a molecule, specifically, 99mTc-mononuclear complex-conjugated bisphosphonate. Some of the 99mTc-mononuclear complex-conjugated bisphosphonate compounds showed superior biodistribution in preclinical studies. Moreover, the drug design concept could be applied to 68Ga PET bone imaging agents. These studies would provide useful information for the development of radiometal-based imaging and therapeutic agents for bone disorders such as bone metastases

Radiolabeled apoptosis imaging agents for early detection of response to therapy

Since apoptosis plays an important role in maintaining homeostasis and is associated with responses to therapy, molecular imaging of apoptotic cells could be useful for early detection of therapeutic effects, particularly in oncology. Radiolabeled annexin V compounds are the hallmark in apoptosis imaging in vivo. These compounds are reviewed from the genesis of apoptosis (cell death) imaging agents up to recent years. They have some disadvantages, including slow clearance and immunogenicity, because they are protein-based imaging agents. For this reason, several studies have been conducted in recent years to develop low molecule apoptosis imaging agents. In this review, radiolabeled phosphatidylserine targeted peptides, radiolabeled bis(zinc(II)-dipicolylamine) complex, radiolabeled 5-fluoropentyl-2-methyl-malonic acid (ML-10), caspase-3 activity imaging agents, radiolabeled duramycin, and radiolabeled phosphonium cation are reviewed as promising low-molecular-weight apoptosis imaging agents

Well-designed bone-seeking radiolabeled compounds for diagnosis and therapy of bone metastases

Bone-seeking radiopharmaceuticals are frequently used as diagnostic agents in nuclear medicine, because they can detect bone disorders before anatomical changes occur. Furthermore, their effectiveness in the palliation of metastatic bone cancer pain has been demonstrated in the clinical setting. With the aim of developing superior bone-seeking radiopharmaceuticals, many compounds have been designed, prepared, and evaluated. Here, several well-designed bone-seeking compounds used for diagnostic and therapeutic use, having the concept of radiometal complexes conjugated to carrier molecules to bone, are reviewed. © 2015 Kazuma Ogawa and Atsushi Ishizaki

Radiolabeled Apoptosis Imaging Agents for Early Detection of Response to Therapy

Since apoptosis plays an important role in maintaining homeostasis and is associated with responses to therapy, molecular imaging of apoptotic cells could be useful for early detection of therapeutic effects, particularly in oncology. Radiolabeled annexin V compounds are the hallmark in apoptosis imaging in vivo. These compounds are reviewed from the genesis of apoptosis (cell death) imaging agents up to recent years. They have some disadvantages, including slow clearance and immunogenicity, because they are protein-based imaging agents. For this reason, several studies have been conducted in recent years to develop low molecule apoptosis imaging agents. In this review, radiolabeled phosphatidylserine targeted peptides, radiolabeled bis(zinc(II)-dipicolylamine) complex, radiolabeled 5-fluoropentyl-2-methyl-malonic acid (ML-10), caspase-3 activity imaging agents, radiolabeled duramycin, and radiolabeled phosphonium cation are reviewed as promising low-molecular-weight apoptosis imaging agents

新規アポトーシスイメージング剤による癌・虚血再灌流障害治療効果超早期診断法の確立

金沢大学学際科学実験センターアポトーシスは生体のホメオスタシスの維持に重要な役割を果たしていることが知られており、アポトーシスを体外から非侵襲的にイメージングすることが可能であれば、これら疾患の臨床診断、病態解明に非常に有用である。昨年度の研究にて、生体内で安定であり、かつ代謝物が代謝臓器から速やかにクリアランスされることが予想されるbis(benzohydroxamamide)誘導体の^Tc錯体[^Tc-C_3(Bham)_2]とAnnexin A5とをリンカーを介して結合した^Tc-C_3(Bham)_2-Annexin A5を作製し、Annexin A5の生理活性を調べたところ、既存の化合物である^Tc-HYNIC-Annexin A5とほぼ同程度の生理活性を示した。今年度の研究にて、この標識体のノーマルマウスにおける体内放射能分布を調べた結果、^Tc-C_3(Bham)_2-Annexin A5の血液クリアランスは^Tc-HYNIC-Annexin A5よりも遅く、^Tc-HYNIC-Annexin A5が非常に高い放射能集積を示す臓器である腎臓において、大きく放射能集積を低減させた。また、肝臓においては、投与早期においては、^Tc-C_3(Bham)_2-Annexin A5は、^Tc-HYNIC-Annexin A5よりも高い放射能集積は示したが、^Tc-HYNIC-Annexin A5の放射能が滞留を示すのに対し、^Tc-C_3(Bham)_2-Annexin A5の放射能は時間経過とともに低減し、投与後6時間後における放射能は同程度であった。以上の結果より、^Tc-C_3(Bham)_2-Annexin A5はアポトーシスイメージング剤として有用である可能性が示された。今後、担癌動物に抗癌剤を投与した時のアポトーシスのイメージングを行う予定である。研究課題/領域番号:18790879, 研究期間(年度):2006 – 2007出典：「新規アポトーシスイメージング剤による癌・虚血再灌流障害治療効果超早期診断法の確立」研究成果報告書　課題番号18790879（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-18790879/)を加工して作

In Vivo and in Vitro Characteristics of Radiolabeled Vesamicol Analogs as the Vesicular Acetylcholine Transporter Imaging Agents

金沢大学疾患モデル総合研究センターThe vesicular acetylcholine transporter (VAChT), a presynaptic cholinergic neuron marker, is a potential internal molecular target for the development of an imaging agent for early diagnosis of neurodegenerative disorders with cognitive decline such as Alzheimer\u27s disease (AD). Since vesamicol has been reported to bind to VAChT with high affinity, many vesamicol analogs have been studied as VAChT imaging agents for the diagnosis of cholinergic neurodeficit disorder. However, because many vesamicol analogs, as well as vesamicol, bound to sigma receptors (σ1 and σ2) besides VAChT, almost all the vesamicol analogs have been shown to be unsuitable for clinical trials. In this report, the relationships between the chemical structure and the biological characteristics of these developed vesamicol analogs were investigated, especially the in vitro binding profile and the in vivo regional brain accumulation. © 2018 Kazuma Ogawa and Kazuhiro Shiba

Induction of Experimental Atrophic Gastritis by N-Methyl-N'-Nitro-N-Nitrosoguanidine or Taurocholic Acid in Donryu Rats

The morphology of the rat (Donryu) gastric mucosa was examined by light microscopy after administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or taurocholic acid (TCA), a component of bile acids. MNNG was given to rats ad libitum from light-sealed bottles for 5 months and deionized water was given freely for 6 months thereafter. TCA was administered to rats freely for 11 months. Deionized water was given to rats as control (non-treated rats). Rats treated with MNNG or TCA and control rats were killed at 11 months after the beginning of the experiment. Using 3 micron tissue samples taken from the area of the gastric mucosa designated before the experiment, hematoxylin and eosin and azan stain were made for histopathological evaluation and fibrosis. Marked atrophic changes, such as reduction in the number of parietal cells, shortened mucosa! length, inflammaotry cell infiltration, and proliferation of fibrosis, were present in the gastric mucosa of rats treated with MNNG as well as TCA. These findings were typical for atrophic gastritis. Such atrophic changes were slight in the gastric mucosa of the control rats. The frequency of tumourous lesions was very low in MNNG-treated rats. We have concluded on the basis of the present data that MNNG as well as TCA can induce atrophic gastritis in Donryu rats

Learning suction graspability considering grasp quality and robot reachability for bin-picking

Deep learning has been widely used for inferring robust grasps. Although human-labeled RGB-D datasets were initially used to learn grasp configurations, preparation of this kind of large dataset is expensive. To address this problem, images were generated by a physical simulator, and a physically inspired model (e.g., a contact model between a suction vacuum cup and object) was used as a grasp quality evaluation metric to annotate the synthesized images. However, this kind of contact model is complicated and requires parameter identification by experiments to ensure real world performance. In addition, previous studies have not considered manipulator reachability such as when a grasp configuration with high grasp quality is unable to reach the target due to collisions or the physical limitations of the robot. In this study, we propose an intuitive geometric analytic-based grasp quality evaluation metric. We further incorporate a reachability evaluation metric. We annotate the pixel-wise grasp quality and reachability by the proposed evaluation metric on synthesized images in a simulator to train an auto-encoder--decoder called suction graspability U-Net++ (SG-U-Net++). Experiment results show that our intuitive grasp quality evaluation metric is competitive with a physically-inspired metric. Learning the reachability helps to reduce motion planning computation time by removing obviously unreachable candidates. The system achieves an overall picking speed of 560 PPH (pieces per hour).Comment: 18 pages, 2 tables, 7 figure