LHRH-II Analog Design: Structure-Function Studies Toward the Development of a LHRH-II Based Radiotherapeutic Agent

摘要

The success of treating neuroendocrine tumors with somatostatin binding peptides linked to a ~(177)Lu-chelate, such as [~(177)Lu-DOTA~0,Tyr~3]Octreotate [1] has stimulated the search for other Gcoupled receptors appropriate for radiotherapy [2]. The observation of extrapituitary LHRH receptors on cancer cells has led to the investigation of this receptor. There is evidence that cancer cells may have abundant low affinity LHRH binding-sites as well as much fewer high affinity binding-sites [3]. LHRH-I and its analogs have been studied more extensively than LHRH-II. Not surprisingly, LHRH-I analogs have been conjugated to cytotoxic drugs (e.g. Doxorubicin) particularly at position-6 for targeted chemotherapy of cancer. In a recent report [4], the in vitro binding of LHRH-I analogs derivatized on Dlys~6 with [~(68)Ga]DO3A10CM or βAla-[~(18)F]FBOA to several tumor lines, including ovarian cancer (EFO-27) cells, were reported. High non-specific binding, low levels of LHRH-I receptor expression in vitro and poor uptake in tumors in vivo were observed. As the binding affinity and activity of LHRH-II analogs for peripheral sites is reported to be similar or superior to LHRH-I and the anti-proliferative effects of LHRH-II on ovarian cancer cells at various doses (1 nM to 10 mM) are similar to that of LHRH-I, [5] we attempted to prepare radiometal derivatized LHRH-II derivatives, for which little has been reported.