Improvement of Pharmacokinetics of Radioiodinated Tyr³-Octreotide by Conjugation with Carbohydrates

Abstract

Among a variety of other factors, the clearance kinetics and routes of excretion of radiopharmaceuticals are of crucial importance for early and high tumor/background ratios and thus signal intensity in diagnostic imaging by single photon emission tomography (SPECT) or positron emission tomography (PET). To overcome the unfavorable pharmacokinetics of radiohalogenated octreotide analogues, we evaluated three carbohydrated conjugates of Tyr(3)-octreotide (TOC). Glucose ([(125)I]Gluc-TOC), maltose ([(125)I]Malt-TOC), and maltotriose ([(125)I]Mtr-TOC) derivatives of [(125)I]TOC were synthesized via Maillard reaction and subsequent radioiodination. In cells transfected with sst1-sst5, I-Malt-TOC, and I-Mtr-TOC show sst-subtype binding profiles similar to I-TOC with high affinity for sst2. Comparative biodistribution studies 10, 30, and 60 min pi in nude mice bearing rat pancreatic tumor xenografts showed fast blood clearance for all glycosylated derivatives. Due to their markedly increased hydrophilicity, [(125)I]Gluc-TOC and [(125)I]Malt-TOC were mainly cleared via the kidneys, which led to a significant decrease in activity accumulation in liver and intestine (5.3 and 1.4 versus 10.6%ID/g for [(125)I]TOC in the liver, 1.7 and 1.0 versus 3.8%ID/g for [(125)I]TOC in the intestine 60 min pi). For all compounds, hydrophilicity and uptake in liver and intestines correlate. Uptake of the carbohydrate conjugates in the kidney was comparable. Compared to the parent compound, the accumulation of the carbohydrated compounds in sst-rich tissues (pancreas, adrenals) was increased by a factor of 1.5-3.5. While tumor uptake of [(125)I]TOC (6.7 +/- 2.6%ID/g), [(125)I]Malt-TOC (5.3 +/- 1.9%ID/g), and [(125)I]Mtr-TOC (4.9 +/- 2.2%ID/g) at 30 min postinjection was comparable, accumulation of [(125)I]Gluc-TOC was significantly increased (10.1 +/- 2.8%ID/g at 30 min pi). Somatostatin receptor specificity of tumor uptake was confirmed by pretreatment, competition, and displacement experiments in vivo using 0.8 mg TOC/kg and gamma-camera imaging. Glycosylation proved to be a powerful tool for the development of high affinity sst ligands with excellent excretion profiles and improved tumor accumulation.

First 18F-Labeled Tracer Suitable for Routine Clinical Imaging of sst Receptor-Expressing Tumors Using Positron Emission Tomography

“…1) [1][2][3][4][5] has been determined ( Table 2). The corresponding 19 F reference compounds all showed very high hsst 2 affinity comparable with that of native somatostatin 28, including no affinity to hsst 1 , very low affinity to hsst 3 , and moderate affinity to hsst 4 and hsst 5 . Compared with iodinated Tyr 3 -octreotide, which is used as the internal reference in the dual tracer internalization studies performed in this study, the hsst 2 affinity of Gluc-Lys(FP)-TOCA, Gluc-S-Dpr(FP)TOCA, and Gluc-S-Dpr(FBOA)TOCA is decreased by a factor of two, whereas it is comparable for the Cel-S-Dpr(FBOA) analog.…”

“…It has been demonstrated for a series of glycosylated, radioiodinated TOC derivatives that the extent of hepatic and intestinal accumulation correlates with ligand lipophilicity (19 18 F-labeled TOCA derivatives investigated in this study (Fig. 7).…”

In Vivo Evaluation of 18F-SiFAlin–Modified TATE: A Potential Challenge for 68Ga-DOTATATE, the Clinical Gold Standard for Somatostatin Receptor Imaging with PET

“…3A) because of the highly lipophilic character of the SiFA synthon. The introduction of a carbohydrate moiety (30) (Fig. 3B).…”

Radionuclide Therapy via SSTR: Future Aspects from Experimental Animal Studies

“…NOTA octreotide (IMP466) labelled with 18 F, or 68 Ga, is readily taken up by AR42J on mice resulting in high tumour/kidney ratios [65]. Glycosylated octreotide analogues have been labelled with 211 At, or 125 I, with maintained SSTR2 affinity and improved pharmacokinetics in AR42J-bearing rats [66,67]. 213 Bi-labelled DOTATOC has been produced and given promising therapeutic results in one animal model [68].…”