Nuclear medicine is engaged with the detection of
pathological processes with the help of
radionuclides. An interesting approach is to target
antigens,
symporters, or receptors with diagnostic and therapeutic
radionuclides. Different
peptide receptors like
somatostatin,
bombesin/GRP or VIP are (over)expressed on
cancer cells, and are therefore an ideal target for the diagnosis and
therapy in nuclear medicine with radiolabeled
peptides. The
somatostatin analogue
OctreoScan [
octreotide coupled with
diethylene-triamine-pentaacetate (
DTPA)] can be labeled with In-111 and is widely used in nuclear oncology for the staging of different
tumors (e.g.,
carcinoids). Other
peptides like
neurotensin,
bombesin/GRP, and VIP are under (pre)clinical investigations. The staging of metastatic
medullary thyroid cancer (MTC) with the conventional radiological procedures is sometimes difficult. The high sensitivity of the
pentagastrin stimulation test in detecting primary or metastatic MTC indicates the presence of
tumor, but its localization is often not possible. This reaction of the
tumor cells to the
pentagastrin stimulation test suggests a widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated
cholecystokinin (CCK)-B/
gastrin receptors not only in over 90% of MTCs, but in a high percentage of small cell
lung cancers, stromal ovarian, and potentially a variety of other
tumors, including gastrointestinal
adenocarcinomas,
neuroendocrine tumors, and
malignant glioma. The aim of our recent work was to develop and systematically optimize suitable radioligands for targeting
CCK-B receptors in vivo and to investigate their role in the staging and
therapy of MTC and other
CCK-B receptor expressing
malignancies. For this purpose, a variety of CCK/
gastrin-related
peptides, all having in common the C-terminal
CCK receptor binding tetrapeptide sequence -Trp-Met-Asp-PheNH(2) or derivatives thereof, were investigated. They were members of the
gastrin- or
cholecystokinin families, or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied and optimized in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in preclinical models. Best
tumor uptake and
tumor-to-nontumor ratios were obtained with members of the
gastrin family, due to their superior selectivity and affinity for the
CCK-B receptor subtype. Radiometal-labeled derivatives of
minigastrin showed excellent targeting of
CCK-B receptor expressing tissues in animals and healthy human volunteers. Preclinical
therapy experiments in MTC-bearing animals showed significant antitumor efficacy. In a subsequent clinical study, 75 MTC patients with metastatic MTC were investigated; 43 suffered of known, 32 of occult disease.
CCK-B receptor scintigraphy was performed with (111)In-DTPA-D-Glu(1)-minigastrin. The normal organ uptake was essentially confined to the stomach (and to a lower extent, to the gallbladder and, in premenopausal women, to normal breast tissue) as a result of
CCK-B receptor specific binding, and to the kidneys as excretory organs. All
tumor manifestations known from conventional imaging were visualized as early as 1 h p.i., with increasing
tumor-to-background ratios over time; at least one lesion was detected in 29/32 patients with occult disease (patient-based sensitivity 91%). Among them were local recurrences, lymph node, pulmonary, hepatic, splenic, and bone (marrow)
metastases. Eight patients with advanced metastatic disease were injected in a dose-escalation study with potentially therapeutic activities of a (90)Y-labeled
minigastrin derivative at 4-6-weekly intervals (30-50 mCi/m(2) per injection for a maximum of four
injections). Hematologic and renal were identified as the dose-limiting toxicities at the 40 and 50 mCi/m(2) levels. Two patients experienced partial remissions, 4 stabilization of their previously rapidly progressing disease. These data suggest that
CCK-B receptor ligands may be a useful new class of receptor binding
peptides for diagnosis and
therapy of a variety of (
CCK-B receptor expressing)
tumor types. They allow for a sensitive and reliable staging of patients with metastatic MTC. Initial therapeutic results are promising, but nephrotoxicity is a major concern to be solved.