-(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

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.