Biological Characterisation of [⁶⁷Ga] or [⁶⁸Ga] Labelled DFO-Octreotide (SDZ 216-927) for PET Studies of Somatostatin Receptor Positive Tumors

Abstract

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.

Siderophores for molecular imaging applications

“…67 Ga-DF-folate(gamma) exhibited specific uptake and was proposed as a diagnostic agent for noninvasive imaging of folate receptor-positing tumours [75]. 67/68 Ga-DFO-Octreotide (SDZ 216-927), comprising DFO coupled to octreotide via a succinyl linker [76,77], showed specific uptake in Somatostatin receptor expressing tumour models and was proposed as PET imaging agent. However, in patients 67 Ga DFO-Octreotide radioactivity was detectable in the circulation even after 24 h; the blood clearance curve was much slower than the one of OctreoScan ( 111 In-DTPA-Octreotide) due to relatively high protein binding in human serum [78].…”

68Ga‐PET: a powerful generator‐based alternative to cyclotron‐based PET radiopharmaceuticals

“…DFO has three hydroxamate groups as metal coordinating sites and complexes Ga 3þ rapidly and with high affinity. This chelator displays an -NH 2 group available for coupling to biomolecules, while an alternative approach is the coupling via a succinyl spacer (21,24,25). It has been shown that low concentration of DFO affects the stability of the Ga 3þ -DFO complex.…”

68Ga-PET Radiopharmacy: A Generator-Based Alternative to 18F-Radiopharmacy

“…This chelator displays a -NH 2 group available for coupling to biomolecules. Another approach is the coupling via a succinyl spacer (Maecke et al 1993;Smith-Jones et al 1994;Stolz et al 1994). …”