Radiolabeled bicyclic somatostatin-based analogs: a novel class of potential radiotracers for SPECT/PET of neuroendocrine tumors.
A variety of radiolabeled somatostatin analogs have been developed for targeting of somatostatin receptor (sst)-positive tumors. Bicyclic somatostatin-based radiopeptides have not been studied yet. Hypothesizing that the introduction of conformational constraints may lead to receptor subtype selectivity or may help to delineate structural features determining pansomatostatin potency, we developed and evaluated first examples of this new class of potential radiotracers for imaging or therapy of neuroendocrine tumors.


METHODS
The bicyclic peptides were synthesized by standard solid-phase peptide synthesis. DOTA was coupled to the resin-assembled peptide for labeling with (177)Lu and (68)Ga. Binding affinity and receptor subtype profile were determined using human ssts. Ca(2+) flux, internalization, and efflux were studied in human embryonic kidney (HEK)-sst(2) and HEK-sst(3) cell lines. Biodistribution and PET/CT studies were performed in corresponding nude mice models.


RESULTS
Some of the new analogs showed high affinity for sst(2) and sst(3) and moderate affinity for sst(1), sst(4), and sst(5), while exhibiting agonistic properties. The analog AM3, comprising an octreotide ring and a head-to-tail-coupled Arg-diaminobutyric acid(DOTA) cycle, showed the highest receptor affinity and agonist potency. (177)Lu-AM3 showed high and receptor-mediated uptake in vivo in sst(2) and sst(3) tumors with low background. Kidneys were the only other tissue accumulating radioactivity that could be reduced by a preinjection of lysine. PET/CT studies of (68)Ga-AM3 at 1 h after injection were characterized by clear localization of the tumor, visualization of the kidneys, and negligible background.


CONCLUSIONS
The high rigidity of these new bicyclic somatostatin-based radiopeptides led to agonistic ligands with good affinity for all 5 ssts. The pharmacokinetic data of (177)Lu/(68)Ga-AM3 make this peptide an excellent candidate as an imaging--and especially as a PET--radiotracer.
Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland.
Melpomeni
M
Fani
Andreas
A
Mueller
Maria-Luisa
ML
Tamma
Guillaume
G
Nicolas
Hans R
HR
Rink
Renzo
R
Cescato
Jean Claude
JC
Reubi
Helmut R
HR
Maecke
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D004795:Enzyme Stability; D005260:Female; D005710:Gallium Radioisotopes; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D008187:Lutetium; D051379:Mice; D018358:Neuroendocrine Tumors / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D021381:Protein Transport; D011849:Radioactive Tracers; D011859:Radiography; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D015899:Tomography, Emission-Computed, Single-Photon
D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D011849:Radioactive Tracers; D017481:Receptors, Somatostatin; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D013004:Somatostatin; D008187:Lutetium; D002118:Calcium