TY - JOUR
T1 - Backbone metal cyclization
T2 - Novel 99mTc labeled GnRH analog as potential SPECT molecular imaging agent in cancer
AU - Barda, Yaniv
AU - Cohen, Nasi
AU - Lev, Vered
AU - Ben-Aroya, Nurit
AU - Koch, Yitzhak
AU - Mishani, Eyal
AU - Fridkin, Mati
AU - Gilon, Chaim
PY - 2004/10
Y1 - 2004/10
N2 - Gonadotropin-releasing hormone (GnRH) is a decapeptide secreted to the pituitary where it binds to specific receptors on the gonadotropes to regulate gonadotropic hormones (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) synthesis and secretion. Specific GnRH receptors are overexpressed in breast, prostatic, ovarian, and other tumors. The aim of this study was to synthesize a cyclic GnRH analog with high affinity to GnRH receptors that can be radiolabeled with 99mTc. A precyclic GnRH analog, [Cys-Gly] 1[D-Ala]6[Nα(η-Cys-amino hexyl)] 10GnRH (Gn-2), containing two hemi-chelator groups was synthesized. It was cyclized applying the recently reported backbone metal cyclization (BMC) approach, to obtain cyclo(Re(O)1-10)[Cys-Gly]1[D-Ala] 6[Nα(η-Cys-amino hexyl)]10GnRH (cyclo[Re(O)-Gn-2]). For comparative evaluations, Gn-2 was oxidized on-resin to yield cyclo(S-S,1-10)[Cys-Gly]1[D-Ala]6[N α(η-Cys-amino hexyl)]10GnRH, (cyclo[S-S-Gn-2]). The binding affinity of cyclo[Re(O)-Gn-2] to rat pituitary membranes showed IC50 of 50nM, compared to IC50 = 10 nM in the native GnRH. Cyclo(99mTc(O)1-10)[Cys-Gly]1[D-Ala]6[N α(η-Cys-amino hexyl)]10GnRH (cyclo[ 99mTc(O)-Gn-2]) was synthesized from Gn-2 and showed similar chromatographic behavior to its rhenium surrogate.
AB - Gonadotropin-releasing hormone (GnRH) is a decapeptide secreted to the pituitary where it binds to specific receptors on the gonadotropes to regulate gonadotropic hormones (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) synthesis and secretion. Specific GnRH receptors are overexpressed in breast, prostatic, ovarian, and other tumors. The aim of this study was to synthesize a cyclic GnRH analog with high affinity to GnRH receptors that can be radiolabeled with 99mTc. A precyclic GnRH analog, [Cys-Gly] 1[D-Ala]6[Nα(η-Cys-amino hexyl)] 10GnRH (Gn-2), containing two hemi-chelator groups was synthesized. It was cyclized applying the recently reported backbone metal cyclization (BMC) approach, to obtain cyclo(Re(O)1-10)[Cys-Gly]1[D-Ala] 6[Nα(η-Cys-amino hexyl)]10GnRH (cyclo[Re(O)-Gn-2]). For comparative evaluations, Gn-2 was oxidized on-resin to yield cyclo(S-S,1-10)[Cys-Gly]1[D-Ala]6[N α(η-Cys-amino hexyl)]10GnRH, (cyclo[S-S-Gn-2]). The binding affinity of cyclo[Re(O)-Gn-2] to rat pituitary membranes showed IC50 of 50nM, compared to IC50 = 10 nM in the native GnRH. Cyclo(99mTc(O)1-10)[Cys-Gly]1[D-Ala]6[N α(η-Cys-amino hexyl)]10GnRH (cyclo[ 99mTc(O)-Gn-2]) was synthesized from Gn-2 and showed similar chromatographic behavior to its rhenium surrogate.
KW - Backbone metal cyclization
KW - Prostate cancer
KW - Radiolabeled GnRH analogs
KW - Technetium-99m
UR - http://www.scopus.com/inward/record.url?scp=4644260673&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2004.05.003
DO - 10.1016/j.nucmedbio.2004.05.003
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C2 - 15464394
AN - SCOPUS:4644260673
SN - 0969-8051
VL - 31
SP - 921
EP - 933
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
IS - 7
ER -