desferrioxamine-b-succinyl-phenylalanine(1)-octreotide and Pancreatic-Neoplasms

Radiolabelled analogues of Somatostatin (SRIF) were demonstrated to be useful for conventional gamma-camera imaging of SRIF receptor-positive tumors and their metastases. To evaluate the feasibility of positron emission tomography (PET) or SRIF receptor-positive tumors deferoxamine (DFO) was conjugated to octreotide via a succinyl linker to form a stable conjugate with the gallium isotopes 67Ga and 68Ga. This new octreotide analog, SDZ 216-927, binds specifically and with high affinity to SRIF receptors in vitro (pKi = 8.94 +/- 0.06) and exhibits SRIF like biological properties as demonstrated by the inhibition of growth hormone (GH) release from cultured pituitary cells. SDZ 216-927 was efficiently labelled with 67Ga without affecting high affinity binding to SRIF receptors. Biodistribution studies revealed that [67Ga]SDZ 216-927 was stable in vivo and rapidly cleared from the circulation, as indicated by the low amount of 67Ga detected in the blood four hours post injection (p.i.). SRIF receptor-positive tumors were clearly visualized 10 minutes p.i. in tumor bearing rats. The specificity of ligand binding in vivo was demonstrated i) by the high tumor/non-tumor ratio 4 hours p.i. (tumor/blood 22.3:1, tumor/muscle 64.5:1, tumor/liver 4.0:1, tumor/spleen 16.8:1) and ii) by a significantly lower uptake of radioactivity in the tumor after pretreatment of tumor bearing animals with an excess of unlabelled SDZ 216-927. SDZ 216-927, when labelled with the positron emitting isotope 68Ga, clearly imaged SRIF receptor-positive tumors using positron emission tomography (PET). Therefore quantitative SRIF receptor imaging with PET seems to be possible using this new radiopharmaceutical.

Topics: Animals; Carrier Proteins; Deferoxamine; Gallium Radioisotopes; In Vitro Techniques; Octreotide; Pancreatic Neoplasms; Rats; Receptors, Somatostatin; Tomography, Emission-Computed

When labeled with gamma-emitting radionuclides, somatostatin analogs have the potential to localize somatostatin receptor-positive tumors using gamma camera scintigraphy. We present a somatostatin analog, [DFO]-octreotide (SDZ 216-927), that comprises desferrioxamine B coupled to octreotide via a succinyl linker. This conjugate can be labeled with either 67Ga for gamma scintigraphy or 68Ga for PET imaging. The 67Ga-labeled conjugate is stable in vitro to autoradiolysis over a 24-hr period.. Rats bearing a somatostatin receptor-positive pancreatic islet cell tumor were injected with 20 MBq of 67Ga[DFO]-octreotide (33 GBq 67Ga/mumole).. After 1 hr, the accumulation of 67Ga[DFO]-octreotide was 0.38 +/- 0.08 %ID/g and the tumor-to-nontumor ratios for blood, muscle, liver and intestine were 2.5, 7.4, 1.9 and 1.6, respectively. PET studies with 68Ga[DFO]-octreotide recorded a very rapid accumulation at the tumor and a subsequent residence half-life of about 6 hr.. Gallium-68-[DFO]-octreotide can be used in PET studies to diagnose receptor-positive tumors such as gastroenteropancreatic, small-cell lung and breast tumors.

Topics: Animals; Carcinoma, Islet Cell; Deferoxamine; Humans; In Vitro Techniques; Isotope Labeling; Octreotide; Pancreatic Neoplasms; Rats; Receptors, Somatostatin; Tissue Distribution; Tomography, Emission-Computed

Two new modifications of the somatostatin analog octreotide, designed to hold the gallium isotopes 67Ga and 68Ga (DFO-SMS, Fig. 1a) and 99mTc (PnAO-SMS, Fig. 1b) have been synthesized and evaluated in vitro and in vivo in tumor bearing rats. DFO-SMS can be labeled with 67Ga3+ and 68Ga3+ with high specific activity within less than 30 minutes in a "cold kit" type formulation. The labeled conjugate is stable under physiological conditions. Moreover the binding affinity to somatostatin receptors on rat brain cortex membranes was shown to be retained. In vivo fast tumor localization was demonstrated and the pharmacokinetics proved to be favourable as the main excretion route was via the kidneys. First PET studies with [68Ga]-DFO-SMS showed a rapid accumulation in the tumor and a residence half-life at the tumor site of about 6 hours. PnAO-SMS can be labeled with 99mTc with high radiochemical purity. In vivo the radiotracer accumulates well in the tumor but due to its high lipophilicity, its main excretion route is via the hepatobiliary system.

Topics: Adenoma, Islet Cell; Animals; Binding, Competitive; Cell Membrane; Cerebral Cortex; Deferoxamine; Gallium Radioisotopes; Molecular Structure; Octreotide; Organotechnetium Compounds; Pancreatic Neoplasms; Rats; Receptors, Somatostatin; Technetium; Tissue Distribution; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon