Octreotate Using a Cross-Bridged Macrocyclic Chelator

Purpose: Somatostatin receptors (SSTr) are expressed on many neuroendocrine tumors, and several radiotracers have been developed for imaging these types of tumors. For this reason, peptide analogues of somatostatin have been well characterized. Copper-64 (t1/2 12.7 hours), a positron emitter suitable for positron emission tomography (PET) imaging, was shown recently to have improved in vivo clearance properties when chelated by the cross-bridged tetraazamacrocycle 4,11bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane (CB-TE2A) compared with 1,4,8,11-tetraazacyclotetradecane1,4,8,11-tetraacetic acid (TETA). Experimental Design: CB-TE2A and TETA were conjugated to the somatostatin analogue tyrosine-3-octreotate (Y3-TATE) for evaluation of CB-TE2A as a bifunctional chelator of Cu. The in vitro affinity of each compound for SSTr was determined using a homologous competitive binding assay. In vivo characteristics of both radiolabeled compounds were examined in biodistribution and microPET studies of AR42J tumor-bearing rats. Results: Cu-CB-TE2A-Y3-TATE (Kd 1.7 nmol/L) and Cu-TETA-Y3-TATE (Kd 0.7 nmol/L) showed similar affinities for AR42J derived SSTr. In biodistribution studies, nonspecific uptake in blood and liver was lower for Cu-CB-TE2A-Y3-TATE. Differences increased with time such that, at 4 hours, blood uptake was 4.3-fold higher and liver uptake was 2.4-fold higher for Cu-TETA-Y3-TATE than for Cu-CB-TE2A-Y3-TATE. In addition, 4.4-times greater tumor uptake was detected with Cu-CB-TE2A-Y3TATE than with Cu-TETA-Y3-TATE at 4 hours postinjection. MicroPET imaging yielded similar results. Conclusions: CB-TE2A appears to be a superior in vivo bifunctional chelator of Cu for use in molecular imaging by PET or targeted radiotherapy due to both improved nontarget organ clearance and higher target organ uptake of Cu-CB-TE2A-Y3-TATE compared with Cu-TETAY3-TATE.