Page 129 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis

Albutate-1, a novel long-circulating radiotracer
1. Introduction
Neuroendocrine tumors (NETs) originate mostly from gastroenteropancreatic (GEP) and bronchial tissue [1]. NETs are rare tumors and are often metastasized at the time of diagnosis [2]. NETs typically express high levels of somatostatin receptor subtype 2 (SSTR2). Hence the SSTR2 represents an excellent target for diagnosis and treatment of the disease using high affinity radiolabeled peptide ligands. For nuclear imaging of NETs [111In]In-DTPA-octreotide (Octreoscan ®) has long been the radiotracer of choice. With the aim to improve diagnostic sensitivity, new octreotide analogs were developed that are suitable for labeling with gallium-68 and applied for positron emission tomography (PET), for example [68Ga]Ga-DOTA-Tyr3-octreotide ([68Ga]Ga- DOTA-TOC), [68Ga]Ga-DOTA-Tyr3-octreotate ([68Ga]Ga-DOTA-TATE) and [68Ga] Ga-DOTA-1-Nal3-octreotide ([68Ga]Ga-DOTA-NOC) [3]. For therapy two radiotracers are most commonly used, [90Y]Y-DOTA-Tyr3-octreotide and ([177Lu] Lu-DOTA-Tyr3-octreotate ([177Lu]Lu-DOTA-TATE) [4-6]. Disease-control rates for these therapies are between 68–94% [7]. An increase in progression-free survival and overall survival was reported when compared to the values after chemotherapy and targeted therapy with everolimus and sunitinib [8]. An advantage of [90Y]Y-DOTA-octreotide or [177Lu]Lu-DOTA-TATE therapy is that prior to therapy the target (SSTR2) can be identified and quantified using PET (68Ga) or SPECT (111In) with the tracer. This way, the therapeutic dose delivered to the tumor can be calculated accurately [9, 10]. As there is no 100% complete response rate there is room to enhance the therapeutic efficacy with e.g. higher doses of the radiopharmaceutical, but this is restricted by concomitant higher radiation doses to other organs. The organs at risk for long-term toxicity are predominantly the kidneys and the bone marrow. The renal radiation dose can however be reduced by co-infusion of cationic amino acids (i.e. lysine, arginine) or with the use of a gelatin-based plasma expander (Gelofusine), leaving the bone marrow the main dose-limiting organ for treatment [11, 12]. The blood clearance of [177Lu]Lu-DOTA-TATE in humans is rapid (<10%ID in blood at 3 h post injection) [13]. Reversible plasma protein- binding represents a promising strategy to prolong the circulation time and thus improve the target-localization of rapidly-clearing drugs, including small- size radiopharmaceuticals [14]. A series of albumin-binding entities have been proposed as pharmacokinetic modifiers to enhance the accumulation of small
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