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Radioimmunoscintigraphy (RIS) and radioimmunoguided surgery (RIGS) were assessed for their usefulness in patients with colorectal carcinoma. Twenty-nine patients (18 primary tumours, 10 with a suspicion of recurrence and one colonic diverticulitis) were studied. Radioimmunoscintigraphy was performed 48 and 72 h after the injection of an anti-TAG72 monoclonal antibody (CYT-103) labelled with 111In. Radioimmunoguided surgery was performed between 72 and 96 h post-injection. During surgery, a systematic screening was performed with a hand-held gamma detecting probe and a surgical index (tumour-to-normal tissue) was obtained. There were statistically significant differences between counts in normal tissue versus tumour (P< 0.001) and RIGS was considered positive for the detection of tumour if the ratio between the counts in the area suspicious of tumour and the counts in the normal tissue was greater than 1.5. The overall sensitivity for RIS and RIGS was 71.4 (55.6 in primary tumours and 100 in recurrences) and 82.1 (83.3 in primary tumours and 80 in recurrences), respectively. Radioimmunoguided surgery changed the surgical procedure in two cases with small tumour deposits. Occult regional lymph node involvement in primary tumours was not found; therefore, RIGS, as a complementary technique to RIS, is particularly useful in recurrences and can help the surgeon in the resection of small tumour deposits which are difficult to localize.

Analogues of the previously reported potent and highly selective CCK1 receptor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido-[1,2-c]pyrimidine (2a) were prepared to explore the structural requirements at the Boc-tryptophan domain for CCK1 receptor affinity. Structural modifications of 2a involved the Trp side chain, its conformational freedom, the Boc group, and the carboxamide bond. Results of the CCK binding and in vitro functional activity evaluation showed three highly strict structural requirements:  the type and orientation of the Trp side chain, the H-bonding acceptor carbonyl group of the carboxamide bond, and the presence of the Trp amino protection Boc. Replacement of this acid-labile group with 3,3-dimethylbutyryl or tert-butylaminocarbonyl conferred acid stability to analogues 14a and 15a, which retained a high potency and selectivity in binding to CCK1 receptors, as well as an in vivo antagonist activity against the acute pancreatitis induced by caerulein in rats. Oral administration of compounds 14a and 15a also produced a lasting antagonism to the hypomotility induced by CCK-8 in mice, suggesting a good bioavailability and metabolic stability.

Radioimmunoscintigraphy (RIS) with BW 431/26 monoclonal antibody (MoAb) labelled with 99Tcm(962 MBq) has been performed in 64 patients with colorectal carcinoma, one of them with two independent tumours. The group consisted of 46 primary lesions, 15 pelvic recurrences and four suspected recurrences which were shown to be liver metastases. Imaging of liver was obtained in all patients, but surgical liver examination was performed in only 56 of them. Planar scans were obtained at 4 and 24 h postinjection. Tomographic images were also performed in five patients: The final diagnosis was confirmed in all patients by their clinical course and by findings at surgery and pathology. A comparative study between the RIS results and the final diagnosis gave a global sensitivity in primary tumours and pelvic recurrences of 59.7 with an accuracy of 59.0. When rectal tumours were excluded, the results were 81.1 and 84.9, respectively. In liver metastases the sensitivity was 50, with an accuracy of 85.7 and a specificity of 100. No correlation has been found between CEA serum levels and lesion detection. In conclusion, RIS is a useful technique for the study and localization of colorectal tumours, being also indicated in patients with normal carcinoembryonic antigen (CEA) serum levels and clinical suspicion of illness.

Radioimmunoscintigraphy (RIS) of colorectal carcinoma with a 111In-labelled anti-TAG-72 monoclonal antibody (CYT-103) has been performed in 24 patients with five primary lesions and 10 suspicious of recurrence (in one of these patients two RIS were made). Histopathological confirmation of the disease and surgical liver examination were carried out in all primary tumours and in 12 possible recurrences. In the remaining eight patients a final diagnosis was established according to the clinical course and other diagnostic procedures. Planar and tomographic scans were obtained at 48 and 72 h postinjection in all patients. All primary tumours were detected by RIS. In the group with recurrences confirmed pathologically the results were nine true positive, two true negative and one false positive in a patient affected only with liver disease. The nine true positive studies corresponded to four positive by computed tomography (CT), four negative by CT and one nonconclusive by CT. Surgical liver examination results were 15 true negative and two false negative. No correlation was found between serum levels of carcinoembryonic antigen or TAG-72 and the detection of the lesions. In 10 patients human anti-mouse antibody (HAMA) levels were studied. In conclusion, RIS with an anti-TAG-72 monoclonal antibody is a useful technique for the study and localization of colorectal tumours, mainly in cases of recurrence, being also indicated in patients with normal TAG-72 serum levels.

The synthesis and stereochemical structure−activity relationships of a new class of potent and selective non-peptide cholecystokinin-A (CCK-A) receptor antagonists based on the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine skeleton are described. The most potent member of this series of eight diastereoisomers, (4aS,5R)-2-benzyl-5-[N-[(tert-butoxycarbonyl)-l-tryptophyl]amino]-1,3-dioxoperhydropyrido[1,2-c]pyrimidine, displays nanomolar CCK-A receptor affinity and higher than 8000-fold potency at the CCK-A than at the CCK-B receptor. As CCK-A antagonist, this compound inhibits the CCK-8-evoked amylase release from pancreatic acinar cells at a low concentration, similar to that of the typical antagonist Devazepide. Highly strict stereochemical requirements for CCK-A receptor binding and selectivity have been found. The l-Trp and the 4a,5-trans disposition of the bicyclic perhydropyrido[1,2-c]pyrimidine are essential for binding potency and selectivity.