Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use

In vivo somatostatin receptor scintigraphy using Octreoscan is a valuable m ethod for the visualisation of human endocrine tumours and their metastases . Recently, several new, alternative somatostatin radioligands have been sy nthesised for diagnostic and radiotherapeutic use in vivo. Since human rumo urs are known to express various somatostatin receptor subtypes, it is mand atory to assess the receptor subtype affinity profile of such somatostatin radiotracers. Using cell lines transfected with somatostatin receptor subty pes sst1, sst2, sst3, sst4 and sst5, we have evaluated the in vitro binding characteristics of labelled (indium, yttrium, gallium) and unlabelled DOTA -[Tyr(3)]-octreotide, DOTA-octreotide, DOTA-lanreotide, DOTA-vapreotide, DT PA-[Tyr(3)]-octreotate and DOTA-[Tyr(3)]-octreotate. Small structural modif ications, chelator substitution or metal replacement were shown to consider ably affect the binding affinity. A marked improvement of sst2 affinity was found for Ga-DOTA-[Tyr(3)]-octreotide (IC50 2.5 nM) compared with the Y-la belled compound and Octreoscan, An excellent binding affinity for sst2 in t he same range was also found for In-DTPA-[Tyr(3)]-octreotate (IC50 1.3 nM) and for Y-DOTA-[Tyr(3)]-octreotate (IC50 1.6 nM). Remarkably, Ga-DOTA-[Tyr( 3)]-octreotate bound at sst2 with a considerably higher affinity (IC50 0.2 nM). An up to 30-fold improvement in sst3 affinity was observed for unlabel led or Y-labelled DOTA-octreotide compared with their Tyr(3)-containing ana logue, suggesting that replacement of Tyr(3) by Phe is crucial for high sst 3 affinity. Substitution in the octreotide molecule of the DTPA by DOTA imp roved the sst3 binding affinity 14-fold. Whereas Y-DOTA-lanreotide had only low affinity for sst3 and sst4, it had the highest affinity for sst5 among the tested compounds (IC50 16 nM). Increased binding affinity for sst3 and sst5 was observed for DOTA-[Tyr(3)]-octreotide, DOTA-lanreotide and DOTA-v apreotide when they Were labelled with yttrium, These marked changes in sub type affinity profiles are due not only to the different chemical structure s but also to the different charges and:hydrophilicity of these compounds. Interestingly, even the coordination geometry of the radiometal complex rem ote from the pharmacophoric amino acids has a significant influence on affi nity profiles as shown with Y-DOTA versus Ga-DOTA in either [Tyr(3)]-octreo tide or [Tyr(3)]-octreotate, Such changes in sst affinity profiles must be identified in newly designed radiotracers used for somatostatin receptor sc intigraphy in order to correctly interpret in vivo scintigraphic data. Thes e observations may represent basic principles relevant to the development o f other peptide radioligands.