title: Synthesis and characterisation of [90Y]-Bz-DTPA-oct: a yttrium-90-labelled octreotide analogue for radiotherapy of somatostatin receptor-positive tumours.
abstract: An investigation into the in vitro behaviour of two yttrium-90-labelled somatostatin analogues was performed. Further in vivo characterisation was performed with the most promising agent. A new DTPA-octreotide analogue (Bz-DTPA-oct) was synthesised by coupling a bifunctional DTPA chelator to the N-terminal amine of the D-Phe1 of Tyr3-octreotide. This new SRIF analogue and DTPA-octreotide (OctreoScan) were radiolabelled with 90Y prior to serum stability being evaluated. Receptor binding assays were also performed on the two radioligands using rat cortex membranes. The [90Y]-Bz-DTPA-oct was further evaluated in vivo using tumour-bearing rats. The first conjugate (DTPA-octreotide) bound with a high affinity to SRIF receptors and the 90Y complex was relatively stable in human serum (t1/2 3.8 d for 90Y lost to serum proteins). The second conjugate (Bz-DTPA-oct) also exhibited a high binding affinity to SRIF receptors, but it demonstrated an even slower loss of 90Y to serum proteins (t1/2 12.1 d). The in vivo evaluation of the more stable [90Y]-Bz-DTPA-oct showed a very rapid and high accumulation in somatostatin receptor-positive tumours, which after 1 h resulted in tumour/nontumour ratios of 3.8, 21, and 4.9 (for blood, muscle, and liver, respectively). These tumour/nontumour ratios increased, and were by 24 h postinjection 138, 285, and 6.1 (for blood, muscle, and liver). Yttrium-90-labelled Bz-DTPa-oct is rapidly and selectively accumulated in somatostatin receptor-positive tissue. Octadentate Bz-DTPA-oct could be ligand for 90Y radiotherapy of somatostatin receptor-positive tumours and their metastases.
authors.affiliation: Preclinical Research, Sandoz Pharma AG, Basle, Switzerland. peter.smith-jones@akh-wien.ac.at
authors.forename: P M
authors.initials: PM
authors.lastname: Smith-Jones
authors.forename: B
authors.initials: B
authors.lastname: Stolz
authors.forename: R
authors.initials: R
authors.lastname: Albert
authors.forename: G
authors.initials: G
authors.lastname: Ruser
authors.forename: U
authors.initials: U
authors.lastname: Briner
authors.forename: H R
authors.initials: HR
authors.lastname: Mäcke
authors.forename: C
authors.initials: C
authors.lastname: Bruns
mesh_terms: D000818:Animals; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D015282:Octreotide / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000097:blood / Q000378:metabolism*; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D017481:Receptors, Somatostatin / Q000032:analysis / Q000378:metabolism*; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D007202:Indicators and Reagents; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D015021:Yttrium Radioisotopes; D004369:Pentetic Acid; D015282:Octreotide