Modulation of Pharmacokinetics of Radioiodinated Sugar-Conjugated Somatostatin Analogues by Variation of Peptide Net Charge and Carbohydration Chemistry

Abstract

Sugar conjugation of biooactive peptides has been shown to be a powerful tool to modulate peptide pharmacokinetics. In the case of radiolabeled somatostatin analogues developed for in vivo scintigraphy of somatostatin receptor (sst) expressing tumors, it generally led to tracers with predominant renal excretion and low uptake in nontarget organs, and in some cases also with enhanced tumor accumulation. Especially with respect to endoradiotherapeutic applicability of these tracers, however, understanding the structural requirements for minimal kidney accumulation and maximal tumor uptake is important. The aim of this study was therefore the evaluation of the potential of specific glycoside structures in combination with reduced peptide net charge to reduce kidney accumulation without affecting tumor accumulation. Three glyco analogues of radioiodinated Tyr(3)-octreotate (TOCA) with z = 0 were evaluated in a comparative study using [(125)I]Mtr-TOCA (z = +1), the maltotriose-Amadori analogue of [(125)I]TOCA, as a reference, [(125)I]Glucuron-TOCA, the Amadori conjugate with glucuronic acid, and [(125)I]Gluc-S- and [(125)I]Gal-S-TOCA, the coupling products with glucosyl- and mannosyl-mercaptopropionate. In cells transfected with sst(1)-sst(5), all three new analogues show sst-subtype binding profiles similar to I-Mtr-TOCA with high, but somewhat reduced, affinity for sst(2). In contrast, internalization into sst(2)-expressing cells (in % of [(125)I]Tyr(3)-octreotide ([(125)I]TOC)) as well as the EC(50,R) of unlabeled TOC for internalization determined in dual-tracer experiments are substantially enhanced for [(123)I]Gal-S-TOCA and [(123)I]Gluc-S-TOCA (internalization, 190% +/- 12% and 265% +/- 20%, respectively, vs 168% +/- 6% of [(125)I]TOC for [(123)I]Mtr-TOCA; EC(50,R), 2.62 +/- 0.07 and 2.96 +/- 0.14, respectively, vs 1.81 +/- 0.07 for [(123)I]Mtr-TOCA). The tumor accumulation of [(125)I]Gal-S-TOCA and [(125)I]Gluc-S-TOCA in AR42J tumor-bearing nude mice 1 h p.i. is consequently very high (22.6 +/- 2.2 and 26.2 +/- 5.6%ID/g) and comparable to that of [(125)I]Mtr-TOCA (25.1 +/- 4.4%ID/g). [(125)I]Glucuron-TOCA showed lower uptake in sst-expressing tissues than did [(125)I]Mtr-TOCA, but considerably enhanced accumulation in nontarget organs such as liver, intestine, and kidney. Due to increased lipophilicity, hepatic and intestinal uptake 1 and 4 h p.i. of [(125)I]Gal-S-TOCA and [(125)I]Gluc-S-TOCA was also slightly higher than that of [(125)I]Mtr-TOCA. Kidney accumulation, however, was reduced by approximately 50% for both compounds (2.6 +/- 0.3 and 2.2 +/- 0.4, respectively, vs 4.0 +/- 0.7%ID/g at 1 h p.i.). Because no sugar-specific effect was detected in the latter case, it is concluded that general ligand pharmacokinetics and especially kidney accumulation of the tracers investigated are mainly determined by physicochemical characteristics such as lipophilicity, net charge, and also charge distribution ([(125)I]Glucuron-TOCA vs [(125)I]Gal-S- and [(125)I]Gluc-S-TOCA). With respect to receptor targeting, however...

A series of 2-O-trifluoromethylsulfonyl-d-mannopyranosides as precursors for concomitant 18F-labeling and glycosylation by click chemistry

“…Glycosylation of peptides has often been shown to enhance the biokinetics and in vivo clearance properties of peptides; [15][16][17] however, only a few approaches toward the glycoconjugation of an 18 F-labeled glycosyl donor with target compounds have been described. [18][19][20][21][22][23] Herein, we present the synthesis of a series of 'clickable' mannosides and study their potential as 18 F-labeling precursors in order to develop an efficient concomitant 18 F-labeling and glycosylation strategy for the synthesis of 18 F-peptides that function as PET tracers with improved biokinetics.…”

18F-Labeled Silicon-Based Fluoride Acceptors: Potential Opportunities for Novel Positron Emitting Radiopharmaceuticals

“…[47]. This study, based on the previously successful use of hydrophilic linkers for enhanced tumor uptake and optimized excretion of PET/SPECT imaging peptides introduced by Schottelius and Antunes et al [48–50], established the efficiency of peptide SiFA derivatives with lipophilicity-reducing auxiliaries as a potential strategy for optimized PET imaging. The in vivo investigation of the most promising PEG/glucose-linked derivative ([ 18 F]SiFA-Asn(AcNH- β -Glc)-PEG-Tyr 3 -octrotate – IC 50 (sst2) = 3.3 ± 0.3 nM; Table 2, Entry 4) showed enhanced tumor uptake (7.7% ID/g at 60 min p.i.)…”

Sweetening Pharmaceutical Radiochemistry by18F-Fluoroglycosylation: A Short Review

“…Noteworthy, the glycosylation of biomolecules, such as peptides or proteins, has been frequently shown to improve the in vivo kinetics and stability in blood and to accelerate the clearance of such glycoconjugates in vivo [11–13]. Moreover, it has been shown by numerous examples that glycosylation of peptides with subsequent radiolabeling opens the way to radiotracers with improved in vivo properties [12–16].…”