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  • The ultimate success of multimodal probe in the

    2022-01-13

    The ultimate success of multimodal probe in the inflammation imaging will be dependent on simplicity in synthesis (combining various modules without protection/deprotection), ease of optimization of pharmacological properties (linker group with tunable PEG moiety), co-registration of macroscopic and microscopic images and correlating with the observed inflammatory conditions of a particular disease model. The heptamethine cyanine based fluorescence tracer MHI-148 which has very high sensitivity in near infra red range is highly suitable in that respect, along with specific targeting of FPR receptors which are expressed and signal is amplified only in the inflammatory conditions. In addition small animal in vivo optical and nuclear/MRI imaging can be performed in multimodal fashion to quantitatively assess and qualitatively correlate at cellular level the various phases of inflammation and assess the effectiveness of treatment. Further evaluations are currently ongoing and the in vivo imaging in animals of various inflammatory models will be reported elsewhere. In conclusion synthesis of the first FPR target specific multimodal probe precursor and its metal complexed derivative – for inflammation imaging is described. The new probes were evaluated for in vitro binding to raw Miglitol synthesis indicating their potential use in vivo nuclear/MRI/near infrared optical imaging in inflamed animal models and subsequent microscopic ex vivo tissue/cells localization studies. Acknowledgments
    Introduction Neutrophils play an essential role in innate immunity. In addition to activating phagocytosis and secreting superoxides and hydrolytic enzymes, the neutrophil must be able to chemotax, or migrate toward the source of a chemoattractant [1], [2]. The formyl peptide receptor (FPR) is a chemoattractant G protein-coupled receptor found on the surface of phagocytes and it is thought to play an important role in allowing phagocytic cells to recognize the presence of bacteria [3] and damaged cells, since only eubacteria, mitochondria, and chloroplasts initiate their protein synthesis with formyl-methionine [4]. FPR expressing cells also exhibit chemotaxis toward peptides derived from the GP-41 envelope protein of HIV-1 [5], [6]. A peptide derived from herpes simplex virus type 2 elicited chemotaxis and superoxide production in neutrophils in a process that appeared to involve FPR [7]. In addition, we recently observed that peptides from the proximal membrane region of the fusion proteins of human immunodeficiency viruses 1 and 2, severe acute respiratory syndrome coronavirus, coronaviruses 229E and HKU, and Ebola virus were potent inhibitors of FPR [8]. Thus FPR appears to respond to the presence of virally derived peptides in addition to bacterially derived ones (for a review of ligands affecting FPR see [9]). Two proteins secreted by Staphylococcus aureus are inhibitors of FPR ([10], [11], [12]). Chemotaxis inhibitory factor of S. aureus (CHIPS) inhibits FPR and the C5a receptor and a homologue of CHIPS, FPRL1 inhibitory protein (FLIPr) inhibits FPRL1 and to a lesser extent FPR, but not C5a. The N-terminus of CHIPS is essential for binding to FPR since removal of the n-terminal phenylalanine reduces affinity for FPR ∼1000 fold. Peptides derived from the N-terminus are also inhibitors of FPR but with ∼10,000 fold lower affinity than CHIPS. Polymorphisms in FPR are very common. Sahagun-Ruiz et al. [13] did an extensive haplotype investigation of FPR and reported finding at least 23 haplotypes for FPR. No polymorphisms were found in the closely related receptor FPRL1 [13]. At present there is no explanation for the wide sequence diversity of FPR. Numerous studies have indicated that patients with aggressive periodontitis exhibit a ∼2 fold reduction in chemotaxis toward fMLF [14], [15], [16], [17], [18], [19] indicating that a reduced ability to exhibit chemotaxis toward formyl peptides may be associated with this disease. Several studies have attempted to correlate FPR polymorphisms with aggressive periodontitis but have produced conflicting results [20], [21], [22].