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.