Novel Polar Single Amino Acid Chelates for Technetium-99m Tricarbonyl-Based Radiopharmaceuticals with Enhanced Renal Clearance: Application to Octreotide

Abstract

Single amino acid chelate (SAAC) systems for the incorporation of the M(CO)(3) moiety (M = Tc/Re) have been successfully incorporated into novel synthetic strategies for radiopharmaceuticals and evaluated in a variety of biological applications. However, the lipophilicity of the first generation Tc(CO)(3)-dipyridyl complexes has resulted in substantial hepatobiliary uptake when either examined as lysine derivatives or integrated into biologically active small molecules and peptides. Here we designed, synthesized, and evaluated novel SAAC systems that have been chemically modified to promote overall Tc(CO)(3)L(3) complex hydrophilicity with the intent of enhancing renal clearance. A series of lysine derived SAAC systems containing functionalized polar imidazole rings and/or carboxylic acids were synthesized via reductive alkylation of the epsilon amino group of lysine. The SAAC systems were radiolabeled with (99m)Tc, purified, and evaluated for radiochemical stability, lipophilicity, and tissue distribution in rats. The log P values of the (99m)Tc complexes were determined experimentally and ranged from -0.91 to -2.33. The resulting complexes were stable (>90%) for at least 24 h. Tissue distribution in normal rats of the lead (99m)Tc complexes demonstrated decreased liver (<1 %ID/g) and gastrointestinal clearance (<1.5%ID/g) and increased kidney clearance (>15 %ID/g) at 2 h after injection compared to the dipyridyl lysine complex (DpK). One of the new SAAC ligands, [(99m)Tc]bis-carboxymethylimidazole lysine, was conjugated to the N-terminus of Tyr-3 octreotide and evaluated for localization in nude mice bearing AR42J xenografts to examine tissue distribution, tumor uptake and retention, clearance, and route of excretion for comparison to (111)In-DOTA-Tyr-3-octreotide and (99m)Tc-DpK-Tyr-3-octreotide. (99m)Tc-bis-(carboxymethylimidazole)-lysine-Tyr-3-octreotide exhibited significantly less liver uptake and gastrointestinal clearance compared to (99m)Tc-DpK-Tyr-3-octreotide while maintaining tumor uptake in the same mouse model. These novel chelators demonstrate that lipophilicity can be controlled and organ distribution significantly altered, opening up broad application of these novel SAAC systems for radiopharmaceutical design.

99mTc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen for Molecular Imaging of Prostate Cancer

“…They maintain the same robust and stabile coordination of 99m Tc(CO) 3 as do first-generation SAAC chelates but incorporate carboxylic acid-substituted imidazoles to facilitate rapid renal clearance and diminished hepatobiliary uptake either alone or when conjugated to small molecules (20) and peptides, such as octreotide (21). 99m Tc-MIP-1405 and 99m Tc-MIP-1427 used the CIM chelate, whereas the chelate used for 99m Tc-MIP-1404 and 99m Tc-MIP-1428 was further derivatized by adding an extra carboxylic acid group to the CIM chelate and was designated TIM.…”

“…We recently designed, synthesized, and evaluated a series of novel second-generation single-amino-acid chelators (SAACs) containing functionalized polar imidazole rings to reduce lipophilicity which, either alone or when conjugated to small molecules and peptides, dramatically diminish hepatobiliary uptake and promote renal clearance (21). Here we describe the biologic evaluation of 4 PSMA inhibitors derived from the glutamate-ureaglutamate or glutamate-urea-lysine pharmacophores incorporating our second-generation SAAC chelators CIM (2,29-(2,29-(azanediylbis(methylene))bis(1H-imidazole-2,1-diyl))diacetic acid) or TIM (2,29,2$,2$9-((2,29-(2,29-(azanediylbis(methylene))bis(1H-imidazole-2,1-diyl))bis(acetyl))bis(azanetriyl))tetraacetic acid) and radiolabeled with 99m Tc via technetium tricarbonyl chemistry (16).…”

Effect of bridging anions on the structure and stability of phenoxide bridged zinc dipicolylamine coordination complexes

“…The relatively high lipophilicity of DPA ligands has been reported by nuclear imaging researchers to produce poor pharmacokinetics and they have mitigated this problem by developing DPA analogues with increased hydrophilicity. 10 It should be possible to refine these hydrophilic molecular designs and produce next-generation, membrane impermeable dinuclear zinc bis-DPA complexes with improved cell recognition and bioimaging performance.…”

Biodistribution of99mTc Tricarbonyl Glycine Oligomers

“…This non-sitespecific approach can lead to heterogeneously labeled products with a distribution of modified sites on the peptide, including the molecular recognition site. In attempt to overcome this undesirable conjugation, currently single amino acid chelate (SAAC) systems for the incorporation of the 99m Tc-tricarbonyl-based radiopharmaceuticals have been successfully established into novel synthetic strategies (Maresca et al ., 2010). During the past decade, the field of technetium coordination chemistry has seen a rising interest in the 99m Tc-tricarbonyl core (Schibli et al ., 1998; Schibli et al ., 2001).…”