Radiochemistry and biological evaluation of novel copper-64-labeled bifunctional chelate-somatostatin analog conjugates

Abstract

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Objectives: Recent biodistribution and microPET studies in AR42J tumor bearing male Lewis rats comparing the compounds ⁶⁴Cu-CB-TE2A-Y3-TATE and ⁶⁴Cu-TETA-Y3-TATE revealed that the former compound exhibited better clearance from blood and liver and had greater tumor detection sensitivity.^1,2 Radioactivity was retained however, in the kidney out to 24 h post-injection (p.i.). It was hypothesized that modifying the charge on ⁶⁴Cu-CB-TE2A-Y3-TATE from positive to either neutral or negative would alter the radiotracer’s biodistribution properties and reduce the dose delivered to the kidney. To accomplish this goal two new bifunctional chelators (BFCs) were synthesized and conjugated to Y3-TATE through either a benzamide (BS353) or sulfonamide (BS354) linkage. It was hoped these linkages would create an ionizable proton on the amide located proximally to the tetraazamacrocycle under physiological conditions and alter the charge of the ligand.

Methods: The BFCs were synthesized and conjugated to Y3-TATE to make BS353 and BS354 using solid-phase methods, and these somatostatin analogs were radiolabeled with ⁶⁴Cu. Biodistribution studies were conducted using male Lewis rats bearing AR42J tumors.

Results: Both compounds were obtained in high radiochemical purity with specific activities of 0.2-0.3 mCi/μg after purification. Biodistribution studies revealed that ⁶⁴Cu-BS354 demonstrated comparable clearance through blood, liver and kidney at 24 h p.i. compared to ⁶⁴Cu-BS353 [blood (%ID/g): 0.027±0.003 vs. 0.038±0.004; liver (%ID/g): 0.21±0.016 vs. 0.22±0.027; kidney (%ID/g): 2.54±0.50 vs. 3.10 ±0.25]. However, ⁶⁴Cu-CB-TE2A-Y3-TATE exhibited better clearance from the kidney ((%ID/g): 1.47±0.11) than either ⁶⁴Cu-BS353 or ⁶⁴Cu-BS354 at 24 h post-injection.¹ Tumor specific uptake was observed for ⁶⁴Cu-BS353 [tumor (non-block vs. block) (%ID/g): 3.20±0.39 vs. 0.46±0.045] and ⁶⁴Cu-BS354 [tumor (non-block vs. block) (%ID/g): 2.29±0.76 vs. 0.72±0.07] but uptake was not better than that observed for ⁶⁴Cu-CB-TE2A-Y3-TATE [tumor (%ID/g): 6.12±0.84] at 1 h post-injection.¹

Conclusions: ⁶⁴Cu-BS353 and ⁶⁴Cu-BS354 demonstrated rapid clearance from non-target tissues and substantial uptake in somatostatin positive tumors. However, the clearance and tumor targeting properties of ⁶⁴Cu-CB-TE2A-Y3-TATE were found to be superior to either compound tested. Receptor binding studies are currently underway to compare their binding properties with ⁶⁴Cu-CB-TE2A-Y3-TATE.