Abstract
The high overexpression of cholecystokinin-2 receptors (CCK2R) in tumors, such as medullary thyroid carcinoma, allows for highly specific diagnostic and therapeutic targeting with radiolabeled peptide probes derived from natural ligands for the receptor. Based on the ideal imaging characteristics, high availability and low cost of technetium-99m (99mTc)-labeled radiopharmaceuticals we have developed two hydrazinonicotinic acid (HYNIC) conjugated minigastrin analogs allowing labeling at high specific activity. The CCK2R targeting peptide conjugates show specific amino acid substitutions in the C-terminal receptor-specific sequence with the aim to increase stability and tumor targeting. The CCK2R affinity and the cell uptake of the new radioligands were analyzed using A431 human epidermoid carcinoma cells stably transfected with human CCK2R and mock transfected cells. Metabolic studies in BALB/c mice revealed a high resistance against enzymatic degradation for both radioligands. Biodistribution studies in tumor-xenografted athymic BALB/c nude mice at 1 h and 4 h p.i. showed that the two 99mTc-labeled compounds showed varying uptake in receptor expressing organs, stomach and pancreas (1.3–10.4% IA/g), as well as kidneys, the main route of excretion (7.8–19.9% IA/g). The tumor uptake in A431-CCK2R xenografts was 24.75 ± 4.38% IA/g for [99mTc]Tc-HYNIC-MGS5 and 42.48 ± 6.99% IA/g for [99mTc]Tc-HYNIC-MGS11 at 4 h p.i., whereas the tumor-to-kidney ratio was comparable (2.6–3.3). On demand availability and potential application for radioguided surgery of a 99mTc-labeled minigastrin analog support the further evaluation of these highly promising new compounds.
Highlights
Regulatory peptides exhibiting high target specificity are suitable lead structures, in the field of oncology, for the development of analogs for radionuclide imaging and therapy [1,2]
A highly promising molecular target to develop radiopeptides for diagnostic imaging and targeted radiotherapy (TRT) of medullary thyroid carcinoma (MTC), small cell lung cancer (SCLC), astrocytoma, stromal ovarian cancer, as well as carcinoids and other tumors of neuroendocrine origin is the cholecystokinin-2 receptor (CCK2R) as an increased level of expression is observed in these malignancies [5,6]
Most of the preclinically [10,11,12,13,14,15,16] and clinically [17,18] investigated MG analogs have been conjugated to the bifunctional chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) allowing stable radiolabeling with trivalent radiometals such as Gallium-68, Indium-111 or Lutetium-177 suitable for positron emission tomography (PET), single photon emission computed tomography (SPECT) and TRT
Summary
Regulatory peptides exhibiting high target specificity are suitable lead structures, in the field of oncology, for the development of analogs for radionuclide imaging and therapy [1,2] Such peptide analogs have the advantage of an easy production via well-established solid phase peptide synthesis (SPPS) allowing the conjugation of a chelator for radiolabeling and the introduction of different modifications into the peptide sequence to optimize pharmacokinetics. [99mTc]Tc-EDDA/HYNIC-MG11 ([99mTc]Tc-EDDA/HYNIC-dGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) conjugated to the monodentate ligand hydrazinonicotinic acid (HYNIC) needs additional coligands such as tris(hydroxymethyl)methylglycine (tricine) or ethylenediamine-N,N’-diacetic acid (EDDA) to complete the coordination sphere [25]. The administration of these two 99mTc-labeled MG analogs to patients was well tolerated showing no to only mild side effects. The HaHaddYYddNNiittIiIiooCCnn‐-ccaaooll nnNNjjuu‐-mmggaaeetttteehhyddylGlGaatlltiuuioo-‐nnAAolloaaff-‐tTTthhyyeerrp-‐pGGeepllpyytt-i‐diTTdrereppb-b‐o((NoNnnd-‐MdMbbeeee)t)NwNtwleleeee-‐enAAnAssApps-‐ps((pNNana-‐MMnddee1))‐111N--‐NNNalaaawlll-‐waNNsaHHssy22sny((HHtnhtYYehsNNeiszIIieCCzde‐-MMdtoGGtoeSSve11av11lua)) lawwutaeiitttihhef iaf faufruthrtehresrtasbtailbiizliinzignegffeefcfetcctacnanbebaecahcihevieevde.dT.hTehtewtow9o9m9T9mc‐Tlac-blealbeedleMdGMaGnaalnoaglos gwsewreercehachraacrtaecrtiezreidzeidn ivnitvroitraondanidn ivnivvoiv, oin, cinlucdluindgingrecreecpetoprtoarffaifnfiintyityanadndceclellluupptatkakeeaasssasayys,s,aass wweellll aass mmeettaabboolliicc aanndd bbiiooddiissttrriibbuuttiioonn ssttuuddiieess iinn ttuummoorr-‐xxeennooggrraafftteedd BBAALLBB//ccnnuuddeemmiiccee
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