Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s> Bivalent Ligands Demonstrated for SPeCT <s> Abstract Two galactose derivatives, a monovalent 99m Tc-MAMA-MGal galactoside and a divalent 99m Tc-MAMA-DGal galactoside, were synthesized and radiolabeled in high radiochemical purity (>98%). Dynamic microSPECT imaging and biodistribution study of two traces in normal and liver fibrosis mice showed that the 99m Tc-MAMA-DGal revealed higher specific binding to asialoglycoprotein receptors in liver and then rapidly excreted via both hepatobiliary system and renal clearance. The results suggest that 99m Tc-MAMA-DGal may be used as SPECT probes for noninvasive evaluation of asialoglycoprotein receptor-related liver dysfunction. <s> BIB001 </s> Small Molecule Radiopharmaceuticals – A Review of Current Approaches <s> Bivalent Ligands Demonstrated for SPeCT <s> On the basis of pharmacological behaviour, dopamine receptors are divided into D1 and D2 subtype, which are primarily responsible for several neurophysiological anomalies. Assessment and validation with SPECT based conjugates provides a promising and cost effective insight to detect molecular changes in such neurological diseases. Spiperone, a well known “butryophenone” based D2 receptor antagonist, has been explored to design a novel conjugate for SPECT evaluation. The molecular docking pose analysis of the designed molecule was explored with dopamine D2 receptor. The molecule showed high affinity (−51.318 kcal mol−1) due to conserved interactions with Asp114 and Phe389 of D2 receptor. DTPA with triazaspirodecanone moiety of spiperone was synthesized using bifunctional chelation approach with 88% yield and has been characterized using NMR and mass spectroscopy. The radiolabeling efficiency of 99mTc-DTPA-bis-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one) was 98%. The complex showed appreciable brain uptake in mice. Receptor binding experiments revealed a Kd of 6.26 nM with maximum localization of the conjugate in the striatum. Thus, these studies could be viewed as novel and informative, initial proof-of-concept approach to the field of 99mTc-labeled radioligand design. <s> BIB002
Receptor Imaging Singh et al. (15) demonstrated the proof-of-concept for 5HT1A receptors using homodimeric ligand and validated the ligand as a SPECT imaging agent. Two identical pharmacophores based on 1-(2-methoxyphenyl)piperazine (MPP) were linked using an aliphatic linker of four carbon atoms to the acyclic chelating agent DTPA and validated as SPECT agent after technetium labeling [ 99m Tc-DTPA-bis(MPBA) Figure 2A] . The authors were able to demonstrate (a) 1000 times high selectivity toward 5HT1A receptors than 5HT2A receptors, (b) involvement of both the pharmacophores for bivalent binding using hill slope analysis, and (c) high labeling efficiency. On similar lines, using DTPA as an acyclic chelator for technetium BIB002 , reported the synthesis of bis-triazaspirodecanone ( Figure 2B) . The ligand showed enhanced binding affinity theoretically using docking and MM-GBSA calculations. Furthermore, the compound showed selective striatum uptake in the brain and selective dopamine D2 targeting. Similarly, the divalent ligand with two units of galactose derivatives ( 99m Tc-MAMA-DGal, Figure 2C ) showed higher specific binding to asialoglycoprotein receptors (ASGPR) in dynamic microSPECT imaging and biodistribution studies of liver fibrosis BIB001 . The monovalent ligand 99m Tc-MAMA-MGal was also validated for comparison. The divalent ligand showed better binding affinity in vitro and fast pharmacokinetics.