title: Evaluation of K(HYNIC)(2) as a bifunctional chelator for (99m)Tc-labeling of small biomolecules.
abstract: This study sought to evaluate K(HYNIC)(2) (K = lysine and HYNIC = 6-hydrazinonicotinyl) as a bifunctional chelator for (99m)Tc-labeling of biomolecule. In this study, four K(HYNIC)(2)-conjugated cyclic RGD peptides, K(HYNIC)(2)-RGD(2) (RGD(2) = E[c(RGDfK)](2)), K(HYNIC)(2)-3G-RGD(2) (3G-RGD(2) = Gly-Gly-Gly-E[Gly-Gly-Gly-c(RGDfK)](2)), K(HYNIC)(2)-2P-RGD(2) (2P-RGD(2) = E[PEG4-c(RGDfK)](2), and PEG(4) = 15-amino-4,7,10,13-tetraoxapentadecanoic acid), and K(HYNIC)(2)-3P-RGD(2) (3P-RGD(2) = PEG4-E[PEG4-c(RGDfK)]2) were prepared, and evaluated for their integrin αvβ3 binding affinity. IC(50) values were determined to be 47 ± 2, 35 ± 2, 37 ± 2, 85 ± 2, and 422 ± 15 nM for K(HYNIC)(2)-2P-RGD(2), K(HYNIC)(2)-3P-RGD(2), K(HYNIC)(2)-3G-RGD(2), K(HYNIC)(2)-RGD(2), and c(RGDyK), respectively, against (125)I-echistatin bound to U87MG cells. Macrocyclic complexes [(99m)Tc(K(HYNIC)(2)-RGD(2))(tricine)] (1), [(99m)Tc(K(HYNIC)(2)-3G-RGD(2))(tricine)] (2), [(99m)Tc(K(HYNIC)(2)-2P-RGD(2))(tricine)] (3), and [(99m)Tc(K(HYNIC)(2)-3P-RGD(2))(tricine)] (4) were prepared, and evaluated in athymic nude mice bearing U87MG glioma xenografts for their tumor targeting capability and biodistribution. It was found that 1-4 all had high solution stability and more than two isomers, as evidenced by the presence of multiple radiometric peaks in their radio-HPLC chromatograms. The tumor uptake of 1-4 was 3.78 ± 0.81, 7.46 ± 1.68, 9.74 ± 1.65, and 8.59 ± 1.52%ID/g, respectively, which was completely consistent with trend of integrin α(v)β(3) binding affinity for cyclic RGD peptides. Replacing [(99m)Tc(HYNIC)(tricine)(TPPTS)] (TPPTS = trisodium triphenylphosphine-3,3',3"-trisulfonate) with [(99m)Tc(K(HYNIC)(2))(tricine)] had little impact on radiotracer tumor uptake; but it had significant effect on the uptake of radiotracer in kidneys, lungs, and spleen. The tumor was clearly visualized by SPECT/CT with excellent contrast in a glioma-bearing mouse administered with 4. K(HYNIC)(2) would be particularly useful for (99m)Tc-labeling of small biomolecules with one or more disulfide linkages.
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, IN, USA.
authors.forename: Shundong
authors.initials: S
authors.lastname: Ji
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Shao
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics; D005910:Glioma / Q000000981:diagnostic imaging / Q000378:metabolism; D064593:Heterografts / Q000000981:diagnostic imaging / Q000378:metabolism; D006834:Hydrazines / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism; D009539:Nicotinic Acids / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D013667:Technetium / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D002614:Chelating Agents; D006834:Hydrazines; D009539:Nicotinic Acids; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; D013667:Technetium