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68Ga-Labeled DOTA-conjugated sCCK8[Phe2(p-CH2SO3H),Nle3,6], a sulfated cholecystokinin 8 (sCCK8) peptide derivative.

Authors

Chopra A1.

Source

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2013 Jan 10 [updated 2013 Jan 31].

Author information

1
National Center for Biotechnology Information, NLM, Bethesda, MD 20894

Excerpt

The three subtypes of the cholecystokinin (CCK) receptor (CCKR), designated CCK1R, CCK2R, and CCK2i4svR, belong to the G-protein–coupled receptor family and are classified on the basis of their affinities for the CCK and the gastrin peptides, differential distribution in the tissues, and molecular structure (1). The CCK1R (previously known as CCKA) is found mainly on the peripheral cells of the pancreas and has a 500- to 1,000-fold higher affinity for sulfated CCK8 (sCCK8; contains a sulfated tyrosine (Tyr) residue) compared with the non-sulfated ligand. In addition, CCK1R is expressed mainly in organs of the gastrointestinal tract of rodents, but it is expressed at low levels in humans (2). CCK2R (previously known as CCKB, also designated as the gastrin receptor (GR)) is expressed in the brain, stomach, pancreas, and gallbladder and exhibits an almost equivalent affinity for gastrin and sulfated or non-sulfated CCK. Although CCK1R and CCK2R/GR are expressed in several normal tissues, CCK2R is overexpressed in most cancerous tumors, such as medullary thyroid carcinomas (>90%), astrocytomas (>65%), and stromal ovarian cancers (100%). The CCK2i4svR is a splice variant of the CCK2R that is expressed only in colorectal and pancreatic neoplasms and is not detectable in normal colorectal mucosa (1). Several gastrin and CCK8 analogs that have a high affinity for CCK2R have been developed and labeled with radionuclides for the detection and therapy of these cancers. It has been shown that radiolabeled CCK8 derivatives and minigastrin (MG0; a shorter version of human gastrin 1 that consists of amino acids 5–17 of the parent peptide) can be used with scintigraphy to detect colorectal or pancreatic cancer tumors that overexpress CCK2i4svR (3) or to screen for patients who may benefit from the radiotherapy of this disease (4). In preclinical studies, however, a high uptake of radioactivity in the kidneys was observed with these radiochemicals, and it was concluded that these tracers will be of limited use in humans (5). In addition, the sulfated Tyr residue at position 2 in sCCK8 is rapidly hydrolyzed, and the two methionine (Met) residues at positions 3 and 6 in the peptide can be easily oxidized during radiolabeling procedures or under in vivo conditions (6). Two cyclized MG analogs, cyclo-MG1 and cyclo-MG2, were synthesized, labeled with 99mTc, and evaluated with single-photon emission computed tomography (SPECT) for the detection of tumors that express CCKR (7). Although the two 99mTc-labeled cyclo-compounds were suitable for the detection of tumors, they had low in vitro stability and generated low-quality scintigraphic images because they rapidly degraded under in vivo conditions. Similar observations have been reported with other 99mTc-labeled compounds that were used in clinical trials for the visualization of tumors that overexpressed the CCK2R (8). In an ongoing effort to develop imaging agents that can be used to visualize tumors that express CCK2R, a stabilized sCCK8 derivative was prepared by replacing the sulfated Tyr in the molecule with a sulfated phenylalanine (Phe2(p-CH2SO3H)) and by substituting the Met residues in the peptide with either norleucine (Nle) (sCCK8[Phe2(p-CH2SO3H),Nle3,6]) or homoproparglyglycine (HPG; sCCK8[Phe2(p-CH2SO3H),HPG3,6]) (6). To facilitate the radiolabeling of these compounds with radionuclides such as 111In or 68Ga, the different peptides, including sCCK8, were conjugated with 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA). In one study the sCCK8, sCCK8[Phe2(p-CH2SO3H), sCCK8[Phe2(p-CH2SO3H),Nle3,6] and sCCK8[Phe2(p-CH2SO3H),HPG3,6] peptides were labeled with 111In, and their biodistribution was compared in athymic BALB/c nude mice bearing AR42J cell tumors that express CCK2R (6). In another study, the biodistribution and noninvasive imaging characteristics of [111In/68Ga]-DOTA-sCCK8[Phe2(p-CH2SO3H),Nle3,6] were compared with those of [111In/68Ga]-DOTA-sCCK8 and [111In/68Ga]-DOTA-MG0 in athymic BALB/c nude mice bearing tumors generated from A431 cells transfected with CCK2R (A431-CCK2R cells) (9). This chapter describes studies performed only with the 68Ga-labeled peptides. Results obtained with the 111In-labeled peptides are described in a separate chapter of MICAD (www.micad.nih.gov) (10).

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