Pre‐clinical comparison of [DTPA0] octreotide, [DTPA0,Tyr3] octreotide and [DOTA0,Tyr3] octreotide as carriers for somatostatin receptor‐targeted scintigraphy and radionuclide therapy

We have evaluated the potential usefulness of radiolabelled [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide as radiopharmaceuticals for somatostatin receptor–targeted scintigraphy and radiotherapy. In vitro somatostatin receptor binding and in vivo metabolism in rats of the compounds were investigated in comparison with [111In‐DTPA0] octreotide. Comparing different peptide–chelator constructs, [DTPA0,Tyr3]octreotide and [DOTA0, Tyr3]octreotide were found to have a higher affinity than [DTPA0]octreotide for subtype 2 somatostatin receptors (sst2) in mouse AtT20 pituitary tumour cell membranes (all IC50 values obtained were in the low nanomolar range). In vivo studies in CA20948 tumor‐bearing Lewis rats revealed a significantly higher uptake of both 111In‐labelled [DOTA0,Tyr3]octreotide and [DTPA0,Tyr3]octreotide in sst2‐expressing tissues than after injection of [111In‐DTPA0]octreotide, showing that substitution of Tyr for Phe at position 3 in octreotide results in an increased affinity for its receptor and in a higher target tissue uptake. Uptake of 111In‐labelled [DTPA0]octreotide, [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide in pituitary, pancreas, adrenals and tumour was decreased to less than 7% of control by pre‐treatment with 0.5 mg unlabelled octreotide/rat, indicating specific binding to sst2. Comparing different radionuclides, [90Y‐DOTA0,Tyr3]octreotide had the highest uptake in sst2‐positive organs, followed by the [111In‐DOTA0,Tyr3]octreotide, whereas [DOTA0, 125I‐Try3]octreotide uptake was low compared to that of the other radiopharmaceuticals, when measured 24 hr after injection. Renal uptake of 111In‐labelled [DTPA0]octreotide, [DTPA0, Tyr3]octreotide and [DOTA0,Tyr3]octreotide was reduced over 50% by an i.v. injection of 400 mg/kg d‐lysine, whereas radioactivity in blood, pancreas and adrenals was not affected. Int. J. Cancer 75:406–411, 1998. © 1998 Wiley‐Liss, Inc.

[1]  M. T. Stephenson,et al.  Indium-111-diethylenetriaminepentaacetic acid-octreotide is delivered in vivo to pancreatic, tumor cell, renal, and hepatocyte lysosomes. , 1997, Cancer research.

[2]  T. Visser,et al.  Inhibition of renal uptake of indium-111-DTPA-octreotide in vivo. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[3]  P. Smith-Jones,et al.  Somatostatin analogues for somatostatin-receptor-mediated radiotherapy of cancer. , 1996, Digestion.

[4]  R. Valkema,et al.  Somatostatin receptor: scintigraphy and radionuclide therapy. , 1996, Digestion.

[5]  Wendy S. Becker,et al.  Reduction of the renal uptake of radiolabeled monoclonal antibody fragments by cationic amino acids and their derivatives. , 1995, Cancer research.

[6]  S. Lamberts,et al.  Internalization of the radioiodinated somatostatin analog [125I-Tyr3]octreotide by mouse and human pituitary tumor cells: increase by unlabeled octreotide. , 1995, Endocrinology.

[7]  H. Imura,et al.  Cloning, functional expression and pharmacological characterization of a fourth (hSSTR4) and a fifth (hSSTR5) human somatostatin receptor subtype. , 1993, Biochemical and biophysical research communications.

[8]  M. Berelowitz,et al.  Somatostatin Receptors: Orphan That Found Family and Function , 1993, Molecular and Cellular Neuroscience.

[9]  A. Peters,et al.  Amino acid infusion blocks renal tubular uptake of an indium-labelled somatostatin analogue. , 1993, British Journal of Cancer.

[10]  S. Lamberts,et al.  Dissociation of antiproliferative and antihormonal effects of the somatostatin analog octreotide on 7315b pituitary tumor cells. , 1992, Endocrinology.

[11]  M. Friedman.  Formation, nutritional value, and safety of D-amino acids. , 1991, Advances in experimental medicine and biology.

[12]  T. Visser,et al.  [111In-DTPA-D-Phe1]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation. , 1991, Life sciences.

[13]  J. Klijn,et al.  Receptor scintigraphy with a radioiodinated somatostatin analogue: radiolabeling, purification, biologic activity, and in vivo application in animals. , 1990, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[14]  J. Jowsey,et al.  The deposition of the rare earths in bone. , 1958, Radiation research.

[15]  P. Gullino,et al.  The toxicity of individual essential amino acids and their diastereomers in rats and the effect of blood sugar levels. , 1955, Archives of biochemistry and biophysics.