Leung Kam
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Bv8 is a small protein secreted by frog skin (1). The prokineticins PK1 and PK2, which are mammalian homologs of Bv8, and their G-protein–coupled receptors prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) have been identified and linked to several biological functions such as gut motility, neurogenesis, angiogenesis, circadian rhythms, hematopoiesis, and nociception (2-4). Prokineticins are also associated with pathologies of the reproductive and nervous systems, myocardial infarction, and tumorigenesis. PKR1 shares 33% identity with human neuropeptide Y receptor-2, and PKR1 is expressed in the brain, spleen, prostate, testis, leukocytes, pancreas, adrenal gland, thyroid, salivary gland, pituitary, stomach, small intestine, colon, and rectum. On the other hand, PKR2 is expressed mainly in the ileocecum and discrete nuclei of the central nervous system. PK1 is secreted by endocrine glands, whereas PK2 is highly expressed in the bone marrow, lymphoid organs, and leukocytes, which suggests a role for PK2 in inflammation, immunomodulation, and hematopoiesis. Binding of PK2 to PKR1 has been shown to reduce the pain threshold in sensory neurons and can contribute to inflammatory pain. PK2 is highly expressed by neutrophils and other inflammatory cells as a pronociceptive mediator in inflamed tissues. Several nonpeptidic PK antagonists have been developed for pain reduction and cancer therapy (5). However, noninvasive quantification of PKR1 levels is not available for drug development. A nonpeptidic PKR1 antagonist, -{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5]triazin-2-ylamino]-ethyl}-guanidine (PC-7), which contains a free guanidine group, was labeled with F by reacting the guanidine moiety with -succinimidyl-4-[F]fluorobenzoate ([F]FBA) to form -(4-[F]fluoro-benzoyl)-'-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5]triazin-2-ylamino]-ethyl}-guanidine ([F]PC-10). Jacobson et al. (6) evaluated [F]PC-10 binding in mice injected with complete Freund adjuvant (CFA) to induce inflammatory pain by upregulation of PK2 and PKR1.
Bv8是一种由蛙皮分泌的小蛋白（1）。促动力蛋白PK1和PK2是Bv8的哺乳动物同源物，它们的G蛋白偶联受体促动力蛋白受体1（PKR1）和促动力蛋白受体2（PKR2）已被鉴定，并与多种生物学功能相关，如肠道蠕动、神经发生、血管生成、昼夜节律、造血和伤害感受（2 - 4）。促动力蛋白也与生殖和神经系统疾病、心肌梗死及肿瘤发生有关。PKR1与人神经肽Y受体-2有33%的同源性，PKR1在脑、脾、前列腺、睾丸、白细胞、胰腺、肾上腺、甲状腺、唾液腺、垂体、胃、小肠、结肠和直肠中表达。另一方面，PKR2主要在回盲部和中枢神经系统的离散核中表达。PK1由内分泌腺分泌，而PK2在骨髓、淋巴器官和白细胞中高表达，这表明PK2在炎症、免疫调节和造血中起作用。已表明PK2与PKR1的结合会降低感觉神经元的痛阈，并可能导致炎性疼痛。PK2在中性粒细胞和其他炎症细胞中高表达，作为炎症组织中的一种伤害感受性介质。已经开发了几种非肽类PK拮抗剂用于减轻疼痛和癌症治疗（5）。然而，PKR1水平的非侵入性定量分析在药物开发中尚不可用。一种非肽类PKR1拮抗剂，-{2-[5-(4-氟苄基)-1-(4-甲氧基苄基)-4,6-二氧代-1,4,5,6-四氢-[1,3,5]三嗪-2-基氨基]-乙基}-胍（PC-7），其含有一个游离胍基，通过使胍部分与N-琥珀酰亚胺基-4-[F]氟苯甲酸酯（[F]FBA）反应，用F进行标记，形成-(4-[F]氟苯甲酰)-'-{2-[5-(4-氟苄基)-1-(4-甲氧基苄基)-4,6-二氧代-1,4,5,6-四氢-[1,3,5]三嗪-2-基氨基]-乙基}-胍（[F]PC-10）。雅各布森等人（6）评估了[F]PC-10在注射完全弗氏佐剂（CFA）以通过上调PK2和PKR1诱导炎性疼痛的小鼠中的结合情况。
