First ^99mTc(l)- and ¹⁸⁸Re(l)-carbonyl labeled aptamers

Aim: Aptamers (synthetic oligonucleotides), can be generated by a combinatorial approach (SELEX1) and are promising probes for radiodiagnostic imaging and therapy due to their high affinity and target specificity. The aptamer, TTA1 is characterized by a low nanomolar affinity and a high selectivity for the human matrix protein tenascin-C. Tenascin-C concentration in normal adult matrix tissue is rather low, whereas it is overexpressed in the stroma of a variety of malignant tumors2, making this target potentially suitable as a multi tumor imaging agent. The aim of this study was to evaluate the pharmacokinetic properties of 99mTc(I) and 188Re(I) carbonyl radiometal chelates attached to TTA1 in tumor animal models in vivo. Material and Methods: [Carboxymethyl-(2-ethylsulfanyl-ethyl)-amino]-acetic acid, an appropriate chelating unit for coordination of 99mTc(I) or 188Re(I), was conjugated to the aptamer and a 99mTc(I) carbonyl precursor was synthesized3. Labeling of the aptamer with the 99mTc(I) carbonyl precursor was achieved in 15 min at 100°C. Synthesis of the 188Re(I) carbonyl labeled aptamer was performed in a one pot reaction at 60°C for 30 min. Both, binding affinity for human tenascin-C and in vitro stability in human plasma were measured. The biodistribution and elimination of the 99mTc-tracer was evaluated in a human U251 xenograft NMRI nude mouse model. Results: The radiochemical purity of the products was >95 % after purification by spin dialysis. Reaction yields ranged from 65 % to 72 % for the 99mTc(I) carbonyl labeled aptamer and from 25 % to 35 % for the 188Re(I) carbonyl labeled aptamer. The specific activity of the Tc(I) carbonyl labeled aptamer was 37 MBq/nmol and the stability in human blood plasma proved to be 65 % after incubation at 37°C for 24h. The binding affinity of the compound against human tenascin-C lies in the low nanomolar range. Significant tumor uptake was observed in the U251 tumor xenograft model after i.v. injection of the 99mTc(I) carbonyl complex. Conclusion: Aptamers can be labeled with both 99mTc(I) and 188Re(I) carbonyls in acceptable yields and good purity. Further investigations are ongoing to fully characterize the potential of the compounds for their use as diagnostic and therapeutic agents. Lit: 1. C. Tuerk, L. Gold, Science, 249, 505-510, 1990; 2. H. P. Erickson, M. A. Bourdon, Annu. Rev. Cell Biol., 5, 71-92, 1989; 3. R. Alberto, R. Schibli, A. P. Schubiger, J. Am. Chem. Soc. 121,6076 - 6077, 1999