Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s> Receptor Imaging <s> A novel SiX-dipropargyl glycerol scaffold (X: H, F, or (18) F) was developed as a versatile prosthetic group that provides technical advantages for the preparation of dimeric radioligands based on silicon fluoride acceptor pre- or post-labeling with fluorine-18. Rapid conjugation with the prosthetic group takes place in microwave-assisted click conjugation under mild conditions. Thus, a bivalent homodimeric SiX-dipropargyl glycerol derivatized radioligand, [(18) F]BMPPSiF, with enhanced affinity was developed by using click conjugation. High uptake of the radioligand was demonstrated in 5-HT1A receptor-rich regions in the brain with positron emission tomography. Molecular docking studies (rigid protein-flexible ligand) of BMPPSiF and known antagonists (WAY-100635, MPPF, and MefWAY) with monomeric, dimeric, and multimeric 5-HT1A receptor models were performed, with the highest G score obtained for docked BMPPSiF: -6.766 as compared with all three antagonists on the monomeric model. Multimeric induced-fit docking was also performed to visualize the comparable mode of binding under in vivo conditions, and a notably improved G score of -8.455 was observed for BMPPSiF. These data directly correlate the high binding potential of BMPPSiF with the bivalent binding mode obtained in the biological studies. The present study warrants wide application of the SiX-dipropargyl glycerol prosthetic group in the development of ligands for imaging with enhanced affinity markers for specific targeting based on peptides, nucleosides, and lipids. <s> BIB001 </s> Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s> Receptor Imaging <s> A rapid one-step 18 F labeling reaction with fluoridealuminum complex, which is based on chelation chemistry, has received a surge of interest for 18 F radiolabeling of peptides. In this study, a non-peptidic bivalent integrin αvβ3 antagonist (bivalent-IA) was conjugated with 1,4,7-triazacy- clononane-1,4-diiacetic acid (NODA). A novel 18 F labeled radiotracer, 18 F-bivalent-IA, was developed via one step 18 F� AlF/NODA chelation reaction in aqueous phase with high radiochemical yield (65�75%, decay corrected) and good specific activity (750�850 mCi/μmol). The tumor integrin targeting efficiency and in vivo pharmacokinetic profile of 18 F-bivalent-IA were evaluated in U-87 MG (integrin positive) and MDA-MB- 231 (integrin negative) models by small-animal PET/CT scan followed by a biodistribution study. The PET/CT and ROI results showed high tumor uptake of 18 F-bivalent-IA in U-87 MG tumor-bearing mice from 5 to 120 min p.i. with good contrast, and the U-87 MG tumor uptake values (6.35 ± 0.67%ID/g, at 1 h p.i.) were 6 times higher than those of MDA-MB-231 tumor (1.05 ± 0.12%ID/g, at 1 h p.i.) (P < 0.0001) which correlated with the integrin αvβ3 expression in tumor tissues confirmed by immunohistochemistry. Co-injection of the 18 F-bivalent-IA with 6 nmol (6 μg) of nonradioactive bivalent-IA effectively blocked tumor uptake demonstrating the integrin αvβ3-specificity. In conclusion, the first 18 F labeled non-peptidic bivalent integrin αvβ3 targeting radiotracer, 18 F-bivalent-IA, was developed and proved to be a highly potent and specific PET radiopharmaceutical for noninvasive imaging of integrin αvβ3, which plays a critical role in tumor angiogenesis and metastasis. <s> BIB002
In another study of Hazari et al. BIB001 , bis-MPP ( Figure 2E ) derivative has been synthesized to image serotonin receptors. The duplication of the pharmacophores leads to a supra-additive increase in binding and potency as compared to monovalent analog. Thus, the bis-compound had sub-nanomolar affinity for the receptor, 1000 times more selectivity for 5HT1A as compared to D2, 5-HTT, or 5HT2A. The compound was validated as PET imaging agent. For the imaging of αvβ3, a non-peptidic BL was reported by Wang et al. BIB002 (Figure 2F ). This molecule consisted of two units of antagonist 4-[2-(3,4,5,6-tetrahydropyrimidine-2-lamino)-ethyloxy]benzoyl-2-(S)-aminoethylsulfonyl-amino-h-alanine (IA) and radiolabeled using 18 F-AlF/NODA chelation reaction. NIR imaging probe for αvβ3 (25): Figure 2L was reported for cancer imaging. The non-peptidic small molecule bivalent antagonist demonstrated improved binding avidity relative to the monovalent ligand.