RADIOPHARMACOLOGY 

The Quarterly Journal of Nuclear Medicine 2001 June;45(2):153-9

Copyright © 2009 EDIZIONI MINERVA MEDICA

language: English

New trends in peptide receptor radioligands

Virgolini I. ^{1, 2, 3}, Traub T. ¹, Novotny C. ¹, Leimer M. ¹, Füger B. ¹, Li S. R. ¹, Patri P. ¹, Pangerl T. ¹, Angelberger P. ⁴, Raderer M. ⁵, Andreae F. ¹, Kurtaran A. ¹, Dudczak R. ^{1, 3}

From the Departments of 1) Nuclear Medicine and 5) Oncology, University of Vienna, Vienna 2) Institute of Nuclear Medicine, Lainz Hospital of Vienna 3) Ludwig Boltzmann Institute for Nuclear Medicine University of Vienna 4) Department of Radiochemistry Research Center Seibersdorf, Austria

The ­high ­level expres­sion of som­a­tos­tatin recep­tors (SSTR) on var­ious ­tumor ­cells has pro­vided the molec­ular ­basis for suc­cessful use of radio­lab­eled octre­o­tide/lan­re­o­tide ana­logs as ­tumor ­tracers in ­nuclear med­i­cine. The ­vast ­majority of ­human ­tumors ­seem to ­over-­express the one or the ­other of ­five dis­tinct ­hSSTR sub­type recep­tors. ­Whereas neu­ro­en­do­crine ­tumors fre­quently over­ex­press ­hSSTR2, intes­tinal aden­o­car­cin­omas ­seem to ­over-­express ­more ­often ­hSSTR3 or ­hSSTR4, or ­both of ­these ­hSSTR. In con­trast to 111In-­DTPA-­DPhe1-octre­o­tide (OCTRE­OSCAN®) ­which ­binds to ­hSSTR2 and 5 ­with ­high ­affinity (Kd 0.1-5 nM), to ­hSSTR3 ­with mod­erate ­affinity (Kd 10-100 nM) and ­does not ­bind to ­hSSTR1 and ­hSSTR4, 111In/90Y-­DOTA-lan­re­o­tide was ­found to ­bind to ­hSSTR2, 3, 4, and 5 ­with ­high ­affinity, and to ­hSSTR1 ­with ­lower ­affinity (Kd 200 nM). ­Based on its ­unique ­hSSTR ­binding pro­file, 111In-­DOTA-lan­re­o­tide was sug­gested to be a poten­tial radio­ligand for ­tumor diag­nosis, and 90Y-­DOTA-lan­re­o­tide suit­able for ­receptor-medi­ated radio­nu­clide ­therapy. As ­opposed to 111In-­DTPA-­DPhe1-octre­o­tide and 111In-­DOTA-­DPhe1-Tyr3-octre­o­tide, dis­crep­an­cies in the scin­ti­graphic ­results ­were ­seen in ­about one ­third of (neu­ro­en­do­crine) ­tumor ­patients con­cerning ­both the ­tumor ­uptake as ­well as detec­tion of ­tumor ­lesions. On a molec­ular ­level, ­these dis­crep­an­cies ­seem to be ­based on a “­higher” ­high-­affinity ­binding of 111In-­DOTA-­DPhe1-Tyr3-octre­o­tide to ­hSSTR2. ­Other som­a­tos­tatin ana­logs ­with diver­gent ­affinity to the ­five ­known ­hSSTR sub­type recep­tors ­have ­also ­found ­their way ­into the ­clinics, ­including 99mTc-­HYNIC-octre­o­tide or 99mTc-depre­o­tide (NEO­SPECT®; NEO­TECT®). ­Most of the ­imaging ­results are ­reported for neu­ro­en­do­crine ­tumors (octre­o­tide ana­logs) or non­small ­cell ­lung ­cancer (99mTc-depre­o­tide), indi­cating ­high diag­nostic cap­ability of ­this ­type of ­receptor ­tracers. Con­se­quently to ­their use as ­receptor ­imaging ­agents, ­hSSTR rec­og­nizing radio­lig­ands ­have ­also ­been imple­mented for experi­mental ­receptor-tar­geted radio­nu­clide ­therapy. The ­study “MAU­RI­TIUS” (Mul­ti­center Anal­ysis of a Uni­versal ­Receptor ­Imaging and Treat­ment Initia­tive, a eUro­pean ­Study), a ­Phase IIa ­study, ­showed in ­patients ­with a cal­cu­lated ­tumor ­dose >10 Gy/GBq 90Y-­DOTA-lan­re­o­tide, the ­proof-of-prin­ciple for ­treating ­tumor ­patients ­with ­receptor ­imaging ­agents. ­Overall treat­ment ­results in >60 ­patients indi­cated ­stable ­tumor dis­ease in ­roughly 35% of ­patients and regres­sive dis­ease in 15% of ­tumor ­patients ­with dif­ferent ­tumor ­entities. No ­acute or ­chronic ­severe hemat­o­log­ical tox­icity, ­change in ­renal or ­liver func­tion param­e­ters due to 90Y-­DOTA-lan­re­o­tide, was ­reported. 90In-­DOTA-­DPhe1-Tyr3-octre­o­tide may ­show a ­higher ­tumor ­uptake in neu­ro­en­do­crine ­tumor ­lesions and may there­fore pro­vide ­even ­better treat­ment ­results in ­tumor ­patients, but ­there is ­only lim­ited ­excess to ­long-­term and sur­vival ­data at ­present. ­Besides ­newer ­approaches and ­recent devel­op­ments of 188Re-­labeled radio­lig­ands no clin­ical ­results on the treat­ment ­response is avail­able yet. In con­clu­sion, sev­eral radio­lig­ands ­have ­been imple­mented on the ­basis of pep­tide ­receptor rec­og­ni­tion ­throughout the ­last ­decade. A plen­ti­tude of pre­clin­ical ­data and clin­ical ­studies con­firm “­proof-of-prin­ciple” for ­their use in diag­nosis as ­well as ­therapy of ­cancer ­patients. How­ever, an ­optimal radio­pep­tide for­mu­la­tion ­does not yet ­exist for ­receptor-tar­geted radio­nu­clide ­therapy.