Hellenic Journal of Nuclear Medicine ��� May - August 2009 www.nuclmed.gr 102 Editorial Abstract The development of gallium-68 -1,4,7,10-tetraazacyclodecane- 1,4,7,10-tetraacetic acid (68Ga-DOTA) compounds was made possi- ble due to the chemistry of 68Ga, which matches the pharmacoki- netics of many peptides, specially the chelators DOTA and DOTA- derivatives with the formation of stable 68Ga (3+) complexes. The availability of this tracer from a germanium-68���gallium-68 genera- tor with a relatively long half-life makes it attractive to use in busy nuclear medicine departments, particularly those with limited ac- cess to cyclotrons. The recent clinical experience with 68Ga-pep- tides includes imaging neuroendocrine tumours particularly carci- noid, as well as neuroectodermal tumours such as phaeochromo- cytoma and paraganglioma. In vitro and animal testing are still pro- gressing alongside clinical studies, with promising results in the use of 68Ga-DOTA-rhenium-cyclized alpha-melanocyte stimulating hor- mone (MSH) and 68Ga-DOTA-napamide (NAP) in melanoma, 68Ga- DOTA-PEG(4)-BN(7-14) (PESIN) for the imaging of bombesin recep- tor-positive tumours and 68Ga-ethylene dicysteine-metronidazole (EC-MN) for imaging tumour hypoxia. In addition to tumours, 68Ga- DOTA peptide inhibitor of vascular peptide protein 1(VAP-P1) is be- ing assessed for imaging inflammatory reaction. An additional val- ue following a positive scan is the use of beta emitters labelled to the same peptides for radionuclide treatment. In conclusion, the re- cent introduction of 68Ga-peptides, made available by a convenient 68Ga/68Ge generator, could greatly contribute to the management of a wide range of clinical conditions including tumours and inflam- mation. Keywords: Gallium-68 ��� Peptides ��� Neuroendocrine tumours ��� So- matostatin receptors Radiopharmacy of gallium-68(68Ga) peptides G allium-68 is a metallic positron emitter that can be produced from a generator system consisting of an in- organic and organic matrix immobilizing the parent radionuclide germanium-68 (68Ge), which has a long half-life of 271 days [1]. A variety of mono- and bifunctional chelators have been developed which allow the formation of stable 68Ga(3+) complexes and convenient coupling to biomole- cules [2]. Gallium-68 has suitable physical properties with a high positron yield reaching 89% of all disintegrations, and its half life of 68min matches the pharmacokinetics of many pep- tides and other small molecules owing to a fast clearance, quick diffusion and target localization [3]. In the last decade there has been a significant increase in the development of radiolabelled peptides for diagnostic ap- plications, especially due to simplified methods of purifica- tion. Peptides have fast clearance, rapid tissue penetration, and low antigenicity and can therefore be produced easily and inexpensively [4]. Receptor imaging was inspired by endogenous somato- statin that consists of a family of a 14- and 28-amino acid pep- tide ��� subtypes bold (SS14, SS28) [5]. The synthetic octreotide is an eight-residue somatostatin analogue [6] and octreotate is another analogue, carrying a C-terminal CO(2)H (Thr) in- stead of the CH(2)OH (threoninol) group [7]. Recent developments include the use of DOTA which is a 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid and newer DOTA-derivatives, bifunctional chelate macrolides available for coupling to peptides and also capable of form- ing stable complexes with radiotracers of the metal group such as 111In, 67Ga, 68Ga, 64Cu, 90Y and 177Lu [8, 9]. The DOTA- linked peptides include DOTA-octreotate (DOTATOC) and (DOTA[-2-Na1-Tyr3-Thr-NH28]-octreotide) (DOTA-lanreotide), (DOTA-1-NaI-octreotide) (DOTANOC) and (DOTATATE) (DOTA- Tyr3Thr8-octreotide) [9-11]. Somatostatin receptors The five different somatostatin receptor subtypes (SSTR1-5) that have been characterized are encoded by five genes, which are localized on separate chromosomes. SSTR1-5 ex- hibit high binding affinity to the natural ligands SS-14 and SS- 28. Only receptor subtypes SSTR2 (which can be further di- vided into SSTR2A and SSTR2B), SSTR5 and to a lesser extent subtype SSTR3 have a high affinity for commercially available synthetic analogues and even these differ in their affinity for the various analogues. Somatostatin receptors are expressed in many tissues, and multiple subtypes often coexist in the same cell. Some of these receptors are overexpressed in sev- eral human tumours, especially neuroendocrine tumours (NET) and their metastases [5, 12-14]. The chemical structure, different charges and hydropho- bicity of DOTA-somatostatin tracers, as well as the coordina- tion geometry of the radiometal complex, have a significant influence in SSTR affinity profiles. For instance, DOTATOC, DO- TA-octreotate and DOTATATE are able to induce SSTR2 inter- nalization. DOTA-lanreotide has high affinity for SSTR5, while DOTANOC is relatively recently introduced and shows a high affinity for SSTR2, SSTR3 and SSTR5 [15-17]. Can gallium-68 compounds partly replace 18F-FDG in PET molecular imaging? Margarita Pagou, Imene Zerizer, Adil AL-Nahhas Professor Adil AL-Nahhas, Department of Nuclear Medicine, Hammersmith Hospital, Imperial Healthcare Trust, Du Cane Road, London W12 0HS, United Kingdom, Tel.: 0044 208 3834923, Fax: 0044 208 3831700 E-mail: adil.al-nahhas@imperial.nhs.uk Hell J Nucl Med 2009 12(2): 102-105 ��� Published on line: 28 May 2009 102 C Y M B C Y M B C Y M B C Y M B

www.nuclmed.gr Hellenic Journal of Nuclear Medicine ��� May - August 2009 103 Editorial (CT) and magnetic resonance imaging (MRI) is often difficult, especially at the base of the skull, and additional methods for the characterization of intracranial lesions are needed to avoid a hazardous biopsy. Meningiomas express high con- centration of SSTR2 and are a good model for imaging with 68Ga-DOTATOC. The same group went on to evaluate kinetic parameters in this disease, which allowed a more compre- hensive assessment of tumour biology [24]. Most recently the value of 68Ga-DOTATOC prior to fractionated stereotactic ra- diotherapy (FSRT) in 26 patients has been assessed. The radi- olabelled peptide offered additional information concerning tumour extension, with improvement of target definition for FSRT [25]. Preclinical studies with 68Ga labelled compounds The development of clinical application of 68Ga peptides is unusual in that it preceded pre-clinical animal work. However, the latter is still on-going and in vitro and animal testing with various chelators and compounds are still progressing along- side clinical studies. It has been demonstrated that gallium 67Ga- and 68Ga- DOTA-octapeptides have distinctly better pre-clinical phar- macological performances than 111In-labelled peptides, espe- cially on SSTR2-expressing cells and the corresponding ani- mal models [3]. Gallium-68 and DOTA chelate stably labelled with 3 different forms of antisense oligonucleotides targeting activated human K-ras oncogene was shown to be a conven- ient approach for in vivo imaging and quantification of oligo- nucleotides biokinetics in living animals [26]. In melanoma, 68Ga-DOTA-rhenium-cyclized alpha- melanocyte-stimulating hormone (alpha-MSH) analogue (DOTA-ReCCMSH (Arg11)) is considered a promising agent for early detection in mice bearing B16/F1 melanoma tumour [27]. Likewise, 68Ga-DOTA-NAPamide, a short linear alpha- melanocyte-stimulating hormone analogue, is superior to 111In-DOTA-MSH in targeting melanocortin type 1 receptor in murine models of primary and metastatic melanoma [28]. Clinical experience with 68Ga peptides Hoffmann and colleagues (2001) were the first to demon- strate that 68Ga-DOTATOC PET could identify all lesions in eight patients with carcinoid tumours, whereas indium-111 (111In) octreotide identified 85% of tumours. Quantitative analysis showed higher tumour to non-tumour ratios with low kidney accumulation [18]. Another comparison between the two radiopharmaceuti- cals in a small group of 4 patients with metastatic NET showed that 68Ga-DOTATOC was better in demonstrating smaller lesions with low tracer uptake, especially with tu- mours bearing only a low density of somatostatin receptors [19]. In a larger series of 84 patients with known or suspected NET 68Ga-DOTATOC had a sensitivity of 97%, a specificity of 92% and an overall accuracy of 96% [20]. Semi-quantitative analysis of 68Ga-DOTATOC showed a variable standardized uptake value (SUV) range (0.877-28.07 mean: 8.73), while dynamic quantitative kinetics evaluation (k1: receptor binding k3: cellular internalisation and Vb: frac- tional blood volume) could provide information that may prove vital for the assessment of the therapeutic result after 90Y-DOTATOC [21]. Most of the studies performed were in patients with carci- noid though 68Ga-DOTATATE was also positive in gastrinoma and insulinoma [22] as well as in malignant abdominal para- ganglioma [11]. In our initial report of the use of 68Ga-DOTATATE in neur- oectodermal tumours, we reported on a group of five pa- tients who had previously undergone surgical resection of histologically proven malignant phaeochromocytoma and subsequently presented with clinical and biochemical signs of recurrence. Gallium-68-DOTATATE was positive in all pa- tients while only three patients had positive iodine-123 meta- iodo benzyl guanidine (123I-MIBG). The SUV(max.) for the pos- itive lesions ranged from 4.6 to 10.4 indicating good tumour to background ratio [23] (Fig. 1). Milker-Zabel et al. (2005) reported the first results of the use of 68Ga-DOTATOC in meningiomas in three patients [24]. The diagnosis of meningiomas by computerized tomography Figure 1. Comparative study in a patient with malig- nant paraganglioma. A: Posterior planar image with 123I-MIBG showing faint uptake in 3 lesions in the spine. The adrenals are noted as prominent but normal structures. B: MIP image of 68Ga-DOTATATE showing numerous well-defined and intense lesions involving the base of the skull, left shoulder, multiple vertebrae, mediastinum as well as multiple soft tissue lesions. 103 C Y M B C Y M B C Y M B C Y M B