In vitro and in vivo evaluation of copper-64-octreotide conjugates

Copper-64 (T( 1/2 ) = 12.8 hr) is a reactor-produced radionuclide that has applications in both nuclear medicine imaging by PET and radiotherapy. Octreotide, a somatostatin receptor ligand, has been conjugated with TETA and CPTA, labeled with ⁶⁴Cu, evaluated both in vitro and in vivo and compared to ¹¹¹In-DTPA-D-Phe¹-octreotide. Methods: The carboxylic acid moieties on that bifunctional chelates were conjugated to the N-terminal amine of D-Phe using the linking agents hydroxybenzotriazol (HOBT) and diisopropylcarbodiimide (DIC). Receptor binding assays on all three radiolabeled octreotide conjugates were accomplished in AtT20 mouse pituitary carcinoma cell membranes. In vivo biodistribution was performed using normal Sprague-Dawley rats and Lewis rats carrying a somatostatin receptor-positive rat pancreatic tumor. Results: The binding affinities of ⁶⁴Cu-CPTA-D- Phe¹-octreotide and ⁶⁴Cu-TETA-D-Phe¹-octreotide in AtT20 cell membranes were both greater than ¹¹¹In-DTPA-D-Phe¹-octreotide (K(d), 78.5 pM, 314 pM and 3.28 nM, respectively). In normal rats, ⁶⁴Cu-CPTA-D-Phe¹- octreotide was localized primarily in the liver. Copper-64-TETA-D-Phe¹- octreotide, similar to ¹¹¹In-DTPA-D-Phe¹-octreotide, had moderate uptake in the kidneys; the hepatobiliary uptake was negligible. In rats bearing CA 20948 pancreatic tumors, both ⁶⁴Cu-CPTA-D-Phe¹-octreotide and ⁶⁴Cu- TETA-D-Phe¹-octreotide had uptake in tumors comparable to or better than ¹¹¹In-DTPA-D-Phe¹-octreotide. Conclusion: Of the two ⁶⁴Cu-labeled octreotide conjugates evaluated, ⁶⁴Cu-CPTA-D-Phe¹-octreotide has the highest affinity for the somatostatin receptor; however, the clearance was hepatobiliary with slow excretion. Copper-64-TETA-D-Phe¹-octreotide binds to the somatostatin receptor with five times the affinity of ¹¹¹In- octreotide, has desirable clearance properties (renal clearance with rapid excretion) and is a potential agent for PET imaging of somatostatin receptors.