Proposal of adenosine receptor ligands as new diagnostic probes for myocaridial function by PET

腺苷受体配体作为 PET 心肌功能诊断新探针的建议

• 批准号: 10670883
• 负责人: ISHIWATA Kiichi
• 金额: $ 1.41万
• 依托单位: TOKYO METROPOLITAN INSTITUTE OF GERONTOLOGY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670883/
• 关键词: positron emission tomography; heart; adenosine; adenosine A2a receptor; adenosine transporter; KF19631; C-11; C-11; アデノシンA_<2a>受容体; アデノシントランスポーター

As a new diagnostic technique for myocardial functions by positron emission tomography (PET), positron emitting ligands for adenosine receptors and adenosine transporters were prepared and their potential as in vivo probes was evaluated.As adenosine AィイD22AィエD2 receptor ligands, seven xanthine-type compounds were labeled with ィイD111ィエD1C-methyl iodide. In vivo studies with mice and rats shoed that [ィイD111ィエD1C]KF19631 ([7-methyl-ィイD111ィエD1C]-(E)-1,3-diallyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthine) had the highest affinity for the myocardial adenosine AィイD22AィエD2 receptors. The AィイD22AィエD2 receptors in the heart of rabbits were clearly visualized by PET with [ィイD111ィエD1C]KF19631. In the in vivo blocking study with another ligand [ィイD111ィエD1C]KF17837, it is suggested that the in vivo binding of xanthine-type ligands was different from that of nonxnthine-type ligands. The compounds, which are potentially labeled with radioactive bromine or iodine, were also labeled with ィイD111ィエD1C, b … More ut the receptor-specific uptake by the heart was not found.As an adenosine transporter blocker, [ィイD111ィエD1C]KF21652(3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl-1,2,3,4-tetrahydro-1-[ィイD111ィエD1C]methyl-6-nitro-2,4-dioxoquinazoline) was prepared. In mice the uptake of [ィイD111ィエD1C]KF21652 by the heart decreased with time, and the transporter-mediated uptake of the compound was not observed in the all organs including the heart and brain. On the other hand, in vitro autoradiography showed the binding of [ィイD111ィエD1C]KF21562 to adenosine transporters, but with a high non-specific binding. These results show that the compound is not a suitable PET ligand for mapping adenosine transporter receptors.We concluded that [ィイD111ィエD1C]KF19631 is a suitable PET ligand for mapping myocardial adenosine AィイD22aィエD2 receptors. The clinical application of this ligand is of great interest to understand the regulation and properties of the adenosine receptors in the normal subjects and patients with cardiovascular disease. Less

作为一种新的正电子发射断层扫描（PET）心肌功能诊断技术，制备了腺苷受体和腺苷转运蛋白的正电子发射配体，并评估了它们作为体内探针的潜力。作为腺苷AiiD22AiiD2受体配体，七种黄嘌呤型化合物被标记 ィイD111ィエD1C-碘甲烷。对小鼠和大鼠的体内研究表明，[ィイD111ィエD1C]KF19631（[7-甲基-ィイD111ィエD1C]-(E)-1,3-二烯丙基-7-甲基-8-(3,4,5-三甲氧基苯乙烯基)黄嘌呤）对心肌腺苷具有最高的亲和力ィイD22AィエD2 受体。使用 [ィイD111ィエD1C]KF19631 通过 PET 清晰地观察到兔子心脏中的 AィイD22AィエD2 受体。在用另一种配体[ィイD111ィエD1C]KF17837进行的体内阻断研究中，表明黄嘌呤型配体的体内结合与非黄嘌呤型配体不同。这些化合物可能被放射性溴或碘标记，也被标记为ィイD111ィエD1C，但未发现心脏对受体的特异性摄取。作为腺苷转运蛋白阻滞剂， 制备[ィイD111ィエD1C]KF21652(3-[1-(6,7-二甲氧基-4-喹唑啉基)-4-哌啶基-1,2,3,4-四氢-1-[ィイD111ィエD1C]甲基-6-硝基-2,4-二氧代喹唑啉)。在小鼠中，心脏对 [ィイD111ィエD1C]KF21652 的摄取随着时间的推移而减少，并且在包括心脏和大脑在内的所有器官中均未观察到转运蛋白介导的化合物摄取。另一方面，体外放射自显影显示[ィイD111ィエD1C]KF21562与腺苷转运蛋白结合，但具有高非特异性结合。这些结果表明该化合物不是用于定位腺苷转运蛋白受体的合适PET配体。我们得出结论，[ィイD111ィエD1C]KF19631是用于定位心肌腺苷AィイD22aエD2受体的合适PET配体。该配体的临床应用对于了解正常受试者和心血管疾病患者中腺苷受体的调节和特性具有重要意义。较少的

项目成果

K. Ishiwata et al.: "Further characterization of a CNS adenosine A_<2A> receptor ligand [^<11>C]KF18446 with in nitro autoradiography and in * *uptake"Annals of Nuclear Medicine. in press.

K. Ishiwata等人：“在硝基放射自显影和**摄取中进一步表征CNS腺苷A_ 2A 受体配体[^ 11 C]KF18446”核医学年鉴。

Ishiwata K., Ogi N., Shimada J. Nonaka H., Tanaka A., Suzuki F. and Senda M.: "Further characterization of a CNS adenosine AィイD22aィエD2 receptor ligand [ィイD111ィエD1C]KF18446 with in vitro autoradiography and in vivo tissue uptake."Ann. Nucl. Med.. (in press

Ishiwata K.、Ogi N.、Shimada J. Nonaka H.、Tanaka A.、Suzuki F. 和 Senda M.：“通过体外放射自显影和体内组织摄取进一步表征 CNS 腺苷 AD22aD2 受体配体 [D111D1C ]KF18446 .“Ann.Nucl.Med..（正在出版中

Ishiwata K. et al.: "^<11>C-Labelled ^<16>F18446 : a potential CNS adenosine A_<2A> receptor ligands"Journal of Nuclear Medicine. 41. 345-354 (2000)

Ishiwata K.等人：“^ 11 C-标记的^ 16 F18446：潜在的CNS腺苷A_ 2A 受体配体”核医学杂志。