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111In/68Ga-Labeled DOTA-conjugated cyclo[γ-d-Glu-Ala-Tyr-d-Lys]-Trp-Met-Asp-Phe-NH2 (cyclo-MG1), a minigastrin analog.


Chopra A1.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2012 May 17 [updated 2012 Jul 12].

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


The three subtypes of the cholecystokinin (CCK) receptors (CCKR) belong to the G-protein–coupled receptor family and are classified (CCK1R, CCK2R, and CCK2i4svR) 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 500- to 1,000-fold higher affinity for sulfated CCK compared with the non-sulfated ligand. In addition, the CCK1R is expressed mainly in organs of the gastrointestinal tract of rodents, while it is expressed at low levels in humans (2). The CCK2R (previously known as CCKB) is expressed in the brain, stomach, pancreas, and gallbladder and exhibits an almost equivalent affinity for gastrin and sulfated or non-sulfated CCK (the CCK2R is also known as the gastrin receptor (GR)). Although CCK1R and CCK2R/GR are expressed in various normal tissues, the CCK2R is overexpressed in most tumor tissues, such as medullary thyroid carcinomas (MTC; >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, with no expression in normal colorectal mucosa (1). Several gastrin and CCK analogs that have a high affinity for the CCK2R have been developed and labeled with radionuclides for the detection and therapy of these cancers. It has been shown that radiolabeled CCK derivatives and minigastrin (MG; 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 the CCK2i4svR (3) or to screen for patients who may benefit from the radiotherapy of this disease (4). In preclinical studies, however, these radiochemicals have shown a high uptake of radioactivity in the kidneys, thereby limiting their use in humans (5). Two cyclized MG analogs, cyclo-MG1 (cyclo1,9[γ-d-Glu1,desGlu26,d-Lys9]MG) and cyclo-MG2 (cyclo1,9[γ-d-Glu1,desGlu26,d-Lys9,Nle11]MG) were synthesized, conjugated to metal chelating agents, labeled with 99mTc through ethylenediamine-N,N-diacetic acid/hydrazinonicotinicamide (EDDA/HYNIC) bifunctional chelating agents and evaluated with single-photon emission computed tomography (SPECT) for the detection of tumors that express the CCKRs (6). The two 99mTc-labeled cyclo-compounds were shown to be suitable to detect tumors, but they exhibited low in vitro stability and generated low-quality scintigraphic images due to rapid degradation in vivo. Similar observations have been reported with other 99mTc-labeled compounds that were used in a clinical trial for the visualization of tumors that overexpress the CCK2R (7). In an ongoing effort to develop imaging agents that could be used to visualize tumors that express the CCK2R, two 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated cyclic MG analogs, cyclo[γ-d-Glu-Ala-Tyr-d-Lys]-Trp-Met-Asp-Phe-NH2 (DOTA-cyclo-MG1) and cyclo[γ-d-Glu-Ala-Tyr-d-Lys]-Trp-Nle-Asp-Phe-NH2 (DOTA-cyclo-MG2), were designed for labeling with either 111In (for SPECT imaging) or 68Ga (for imaging with positron emission tomography (PET)) (5). The biodistribution of the various radiolabeled compounds and their ability to detect xenograft tumors that express the CCK2R in mice was then investigated. This chapter presents the results obtained with 111In/68Ga-labeled DOTA-cyclo-MG1 ([111In/68Ga]-DOTA-cyclo-MG1). The biodistribution and imaging characteristics of 111In/68Ga-labeled DOTA-cyclo-MG2 are presented in a companion chapter in MICAD ( (8).

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