title: NODAGATOC, a new chelator-coupled somatostatin analogue labeled with [67/68Ga] and [111In] for SPECT, PET, and targeted therapeutic applications of somatostatin receptor (hsst2) expressing tumors.
abstract: A monoreactive NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) derived prochelator (1-(1-carboxy-3-carbo-tert-butoxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7-triazacyclononane (NODAGA(tBu)(3))) was synthesized in five steps with an overall yield of 21%. It is useful for the coupling to the N-terminus of peptides on solid phase and in solution; it was coupled to [Tyr3]-octreotide (TOC) on solid phase, and the resulting peptide, NODAGA-Tyr3-octreotide (NODAGATOC), was labeled with the radiometals 111In and 67Ga in high yields and good specific activities. [67Ga]- and [111In]-NODAGA-Tyr3-octreotide appear to be useful to visualize primary tumors and metastases which express somatostatin receptors subtype 2 (sstr2), such as neuroendocrine tumors, because of their high affinity to this receptor subtype with IC(50) = 3.5 +/- 1.6 nM and 1.7 +/- 0.2 nM, respectively. NODAGATOC could be used as a SPECT and PET tracer, when labeled with 111In, 67Ga, or 68Ga, and even for therapeutic applications. Surprisingly, [111In]-NODAGATOC shows 2 times higher binding affinity to sstr2, but also a factor of 4 higher affinity to sstr5 compared to [67Ga]-NODAGATOC. [67Ga]-NODAGATOC is very stable in serum and rat liver homogenate. There is no difference in the rate of internalization into AR4-2J rat pancreatic tumor cells; both radioligands are highly internalized, at 4 h a 3 times higher uptake compared to [111In]-DOTA-Tyr3-octreotide ([111In]-DOTATOC) was found. The biodistribution of [67Ga]-NODAGATOC in AR4-2J tumor bearing nude mice is very favorable at short times after injection; there is fast excretion from all nontarget organs except the kidneys and high uptake in sst receptor rich organs and in the AR4-2J tumor. Again it is superior to [111In]-DOTATOC in this respect. The results indicate an improved biological behavior which is likely due to the fact that an additional spacer group separates the chelate from the pharmacophoric part of the somatostatin analogue.
authors: Division of Radiological Chemistry, Institute of Nuclear Medicine, Department of Radiology, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland.
authors: Klaus-Peter
authors: KP
authors: Eisenwiener
authors: M I M
authors: MI
authors: Prata
authors: I
authors: I
authors: Buschmann
authors: Han-Wen
authors: HW
authors: Zhang
authors: A C
authors: AC
authors: Santos
authors: Sandra
authors: S
authors: Wenger
authors: Jean Claude
authors: JC
authors: Reubi
authors: Helmut R
authors: HR
authors: Mäcke
mesh_terms: D000818:Animals; D002478:Cells, Cultured / Q000000981:diagnostic imaging / Q000378:metabolism; D004355:Drug Stability; D005260:Female; D005710:Gallium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring; D066298:In Vitro Techniques; D007205:Indium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008024:Ligands; D008099:Liver / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015282:Octreotide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D005710:Gallium Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D008024:Ligands; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; C045210:3-Tyr-octreotide; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; D015282:Octreotide