Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s> Copper-Based Click Ligation <s> The Click-to-Chelate approach is a highly efficient strategy for the radiolabeling of molecules of medicinal interest with technetium and rhenium-tricarbonyl cores. Reaction of azide-functionalized molecules with alkyne prochelators by the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC; click reaction) enables the simultaneous synthesis and conjugation of tridentate chelating systems for the stable complexation of the radiometals. In many cases, the functionalization of (bio)molecules with the ligand system and radiolabeling can be achieved by convenient one-pot procedures. Since its first report in 2006, Click-to-Chelate has been applied to the development of numerous novel radiotracers with promising potential for translation into the clinic. This review summarizes the use of the Click-to-Chelate approach in radiopharmaceutical sciences and provides a perspective for future applications. <s> BIB001 </s> Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s> Copper-Based Click Ligation <s> In the development of our melanoma-selective delivery approach, three preselected conjugates of 5-iodo-2′-deoxyuridine (IUdR) to the ICF01012 melanoma-carrier were radiolabelled with iodine-125, and their in vivo distribution profile was determined. A radioiodination method for the conjugate 1a and its PEGylated derivatives 1b–c was developed via electrophilic iododestannylation in good radiochemical yield with excellent radiochemical purity (>99%). When administered to melanoma-bearing mice, the PEGylated conjugates exhibited an increased tumour uptake with a prolonged residence time. PEGylation also resulted in enhanced tumour selectivity compared with the non-PEGylated parent. These characteristics support further development of this model to achieve maximal concentration of anticancer therapeutics at the local site of action and minimize distribution to non-targeted sites. <s> BIB002 </s> Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s> Copper-Based Click Ligation <s> First introduced by K Barry Sharpless in 2001, the term ‘click chemistry’ soon became a widely used description of chemical reactions that proceed rapidly, cleanly and in a manner that is often compatible with aqueous solutions. Click chemistry is frequently employed throughout the process of drug discovery, and greatly helps advance research programs in the pharmaceutical industry. It facilitates library synthesis to support medicinal chemistry optimization, helps identify the targets and off-targets of drug candidates, and can facilitate the determination of drug efficacy in clinical trials. In the last decade, a large number of patent applications covering the various types and utilities of click chemistry have been filed. In this review, we provide the first analysis of click chemistry applications. <s> BIB003
Click chemistry as described by K. Barry Sharpless is "a set of powerful, virtually 100% reliable, selective reactions for the rapid synthesis of new compounds" BIB002  . Click chemistry reports in radiopharmaceutical sciences were first published in 2006 BIB001 . It has been extensively studied and published. Many comprehensive reviews are available. Some examples are (a) click chemistry mechanism (45), (b) application in radiopharmaceuticals  BIB001 , (c) application with specific precursors-glycobiology (46), (d) click chemistry in chelate development BIB001 , and (e) patent analysis BIB003 . An overview of click chemistry for radiopharmaceuticals is as follows: . Though most popular as copper (I) catalyzed click chemistry leading to selective formation of 1,4 regioisomer, another variation using ruthenium complexes which leads to selective 1,5 regioisomer has also been explored.