Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s>  <s> The αvβ3 integrin, a transmembrane heterodimeric protein expressed on sprouting endothelial cells, binds to the arginine-glycine-aspartic acid (RGD) amino acid sequence of extracellular matrix proteins such as vitronectin. Growing malignant tumors continuously require angiogenesis. As a result, αvβ3 is preferentially expressed in growing tumors and is a potential target for radiolabeled RGD-peptides. In this study we compared the tumor targeting characteristics of a monomeric radiolabeled RGD-peptide with those of a dimeric analogue. Both peptides were radiolabeled with 99mTc via the hydrazinonicotinamid (= HYNIC) moiety to form 99mTc-HYNIC-c(RGDfK) and 99mTc-HYNIC-E-[c(RGDfK)]2. In vitro, the IC50 showed a 10-fold higher affinity of the dimer for the αvβ3 integrin as compared to the monomer (0.1 vs. 1.0 nM). In athymic female BALB/c mice with subcutaneously growing OVCAR-3 ovarian carcinoma xenografts, tumor uptake peaked at 5.8 ± 0.7 %ID/g and 5.2 ± 0.6 %ID/g for the dimer and the monomer, respectively.... <s> BIB001 </s> Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s>  <s> Integrin αvβ3 plays a significant role in tumor angiogenesis and is a receptor for the extracellular matrix proteins with the exposed arginine-glycine-aspartic (RGD) tripeptide sequence. These include vitronectin, fibronectin, fibrinogen, lamin, collagen, Von Willibrand's factor, osteoponin, and adenovirus particles. Integrin αvβ3 is expressed at low levels on epithelial cells and mature endothelial cells, but it is overexpressed on the activated endothelial cells of tumor neovasculature and some tumor cells. The highly restricted expression of integrin αvβ3 during tumor growth, invasion, and metastasis presents an interesting molecular target for both early detection and treatment of rapidly growing solid tumors. In the past decade, many radiolabeled linear and cyclic RGD peptide antagonists have been evaluated as the integrin αvβ3 targeted radiotracers. Significant progress has been made on their use for imaging tumors of different origin by single photon emission computed tomography (SPECT) or positron... <s> BIB002 </s> Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s>  <s> A new heterobivalent peptide ligand specifically targeting polymorphonuclear leukocytes (PMNs) with favorable pharmacological parameters to monitor sites of inflammation for imaging is designed. The detailed synthesis, characterization, and pharmacological evaluation of the ligands are reported here. Two separate peptide binding ligands for formyl peptide and tuftsin receptors were chosen to link together based on the high expression levels of the two receptors on activated PMNs The heterobivalency and pegylated links were incorporated in the structural design to improve the sensitivity of the detection and to improve the bioavailability along with blood clearance profile, respectively. Two chemical constructs, cFLFLF-(PEG)(n)-TKPPR-(99m)Tc (n = 4, 12), were evaluated in vitro with human PMNs for binding affinity and bioavailability. As a result, cFLFLF-(PEG)(12)-TKPPR-(99m)Tc was found to have more favorable pharmacological properties and was therefore used for further in vivo studies. Preliminary in vivo assessment of the agent was performed using single gamma emission computed tomography (SPECT) imaging of a mouse model of ear inflammation. The results of these studies indicate cFLFLF-(PEG)(12)-TKPPR-(99m)Tc may be a desirable imaging agent for binding to PMNs to identify sites of inflammation by SPECT. <s> BIB003
Radiopharmaceuticals are an integral component of nuclear medicine and are widely applied in diagnostics and therapy. Though widely applied, the development of an "ideal" radiopharmaceutical can be challenging. Issues such as specificity, selectivity, sensitivity, and feasible chemistry challenge the design and synthesis of radiopharmaceuticals. Over time, strategies to address the issues have evolved by making use of new technological advances in the fields of biology and chemistry. This review presents the application of few advances in design and synthesis of radiopharmaceuticals. The topics covered are bivalent ligand approach and lipidization as part of design modifications for enhanced selectivity and sensitivity and novel synthetic strategies for optimized chemistry and radiolabeling of radiopharmaceuticals. Keywords: radiopharmaceuticals, multivalent ligands, bioorthogonal approaches, surface modification, crosscoupling reaction iNTRODUCTiON Radiopharmaceuticals are being used in diagnostics and therapeutics for more than half a century. They are widely used in the delineation of neurodegenerative diseases, myocardial imaging and diagnosis, and treatment of cancer. Due to their wide application, the development of an "ideal" radiopharmaceutical continues to be the foremost challenge of the research frontier in nuclear medicine. The key issues confronting the research community in radiopharmaceutical chemistry is to develop highly specific and selective ligands with high specific activity capable of targeting and overcoming biological barriers. The challenges emanate at the different stages of developing radiopharmaceutical, viz., design, modification, and radiolabeling. Selection of the type of molecule (antibody and their fragments, peptides, nucleosides, aptamers, small molecules), surface modifications, multivalency, and labeling reactions optimization are few variations that have been used to address the challenges. Based on these variations, the review presents three emerging approaches that address the challenges: high selectivity and sensitivity through design optimization using bivalent ligands (BLs), targeting against natural barriers through modification using lipidization, and high specific activity while radiolabeling using sophisticated chemistries, viz., bioorthogonal and cross-coupling reactions. These approaches have the potential to be integrated into radiopharmaceutical development. We describe each of these approaches seriatim in along with avenues for future research in Sections 1-3. Multimeric RGD as integrin αvβ3 targeting unit conjugated to acyclic and cyclic chelators with dimeric, tetrameric, and octameric units BIB001 BIB002 (5) Heterobivalent peptides SPECT imaging agent for neutrophilic inflammation BIB003 Melanocortin receptors peptide-based ligands Bombesin peptide (8) 1. HiGH SeLeCTiviTY THROUGH BivALeNT LiGAND APPROACH