Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s> Tumor Imaging <s> Abstract From the X-ray crystal structures of Ga–DOTA chelates, we were able to deduce that two free carboxylate groups of the radiogallium–DOTA complex may be utilized for coupling to functional moieties that recognize molecular targets for in vivo imaging without reducing the radiogallium-complex stability. Thus, we designed 2,2′-[4,10-bis(2-{[2-(2-methyl-5-nitro-1 H -imidazol-1-yl)ethyl]amino}-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl]diacetic acid (DOTA-MN2) ( 7 ), employing a metronidazole moiety as the recognition site of hypoxic lesions, based on the drug design concept of bifunctional radiopharmaceuticals. Coupling of DOTA-bis( tert -butyl)ester 5 with 1-(2-aminoethyl)-2-methyl-5-nitroimidazole dihydrochloride, followed by deprotection, afforded the required 7 (DOTA-MN2). 67 Ga-labeling was carried out by reaction of DOTA-MN2 with 67 Ga-citrate. When 67 Ga–DOTA-MN2 was incubated in phosphate-buffered saline or mouse plasma, no measurable decomposition occurred over a 24-h period. In biodistribution experiments in NFSa tumor-bearing mice, 67 Ga–DOTA-MN2 displayed not only a significant tumor uptake, but also rapid blood clearance and low accumulations in nontarget tissues, resulting in high target-to-nontarget ratios of radioactivity. These results indicate the potential benefits of the drug design of 67 Ga–DOTA-MN2. The present findings provide helpful information for the development of radiogallium-labeled radiopharmaceuticals for SPECT and PET studies. <s> BIB001 </s> Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s> Tumor Imaging <s> Biomedical applications of semiconductor quantum dots (QDs) are still limited due to the decrease in their photoluminescence (PL) after surface modification for target specificity and in vivo imaging. This is being taken care of by choosing ligands which can enhance the tumour specificity without affecting the optical properties of the core QDs. In this study we have synthesized a dithiocarbamate (DTC) derivatised bisbiotin ligand (DTC–bisbiotin) and then functionalized it covalently over the CdSe–ZnS quantum dot surface to produce the (QD-DTC–bisbiotin) nanobioconjugate. The influence of the size of the QD nanobioconjugate (10–15 nm) and optical properties are evaluated by TEM, UV-Vis and fluorescence spectroscopy and have been found to be favourable for diagnostic imaging studies. The synthesized nanobioconjugate was further studied for its in vivo biodistribution and pharmacokinetics through a pre-targeting approach. In vivo pharmacokinetics and biodistribution studies were performed by radiolabelling the QD nanobioconjugate with 99mTechnetium (99mTcQD-DTC–bisbiotin). 99mTcQD-DTC–bisbiotin showed significantly higher tumour uptake (5% ID g−1) with better tumour retention, high tumour/normal organ contrast and enhanced pharmacokinetics as compared to the native DTC–bisbiotin ligand. This illustrates that although the bivalent effect of bisbiotin ligand is responsible for the tumour uptake, the Enhanced Permeable and Retention (EPR) effect due to the size of the QD nanobioconjugate plays a major role in the enhanced pharmacokinetics and biodistribution. The efficient binding of 99mTc with the QD nanobioconjugate also highlights its use as “a SPECT-optical imaging agent”. <s> BIB002
Bivalent ligand concept has also been validated for metal-based radiopharmaceuticals. Metronidazole was conjugated to DOTA (DOTA-MN2, Figure 2I ) and developed as radiogallium-DOTA complex without reducing the radiogallium complex stability for the imaging of hypoxic lesions using PET/SPECT BIB001 . The complex showed significant tumor uptake and low non-target accumulation. The concept of enhanced binding via multivalency using small molecules and nanoparticles (NPs) has also been reported. Nanoparticles (Quantum dots), as reported in the work of Bag et al. BIB002 , were conjugated with multiple biotin units (bisbiotin) to have enhanced selectivity. Tc-QDDTC-bisbiotin showed significantly higher tumor uptake, better tumor retention, and enhanced pharmacokinetics as compared to DTC-bisbiotin ligand. The work illustrates the bivalent effect of bisbiotin ligand for high tumor uptake. Other effects, viz., better tumor retention and enhanced pharmacokinetics were the results of the enhanced permeable and retention (EPR) effect due to the QD ( Figure 2J ).