Abstract
The success of Lutathera™ ([177Lu]Lu-DOTA-TATE) in the NETTER-1 clinical trial as a peptide receptor radionuclide therapy (PRRT) for somatostatin receptor expressing (SSTR) neuroendocrine tumours (NET) is likely to increase the demand for patient stratification by positron emission tomography (PET). The current gold standard of gallium-68 radiolabelled somatostatin analogues (e.g., [68Ga]Ga-DOTA-TATE) works effectively, but access is constrained by the limited availability and scalability of gallium-68 radiopharmaceutical production. The aim of this review is three-fold: firstly, we discuss the peptide library design, biological evaluation and clinical translation of [18F]fluoroethyltriazole-βAG-TOCA ([18F]FET-βAG-TOCA), our fluorine-18 radiolabelled octreotide; secondly, to exemplify the potential of the 2-[18F]fluoroethylazide prosthetic group and copper-catalysed azide-alkyne cycloaddition (CuAAC) chemistry in accessing good manufacturing practice (GMP) compatible radiopharmaceuticals; thirdly, we aim to illustrate a framework for the translation of similarly radiolabelled peptides, in which in vivo pharmacokinetics drives candidate selection, supported by robust radiochemistry methodology and a route to GMP production. It is hoped that this review will continue to inspire the development and translation of fluorine-18 radiolabelled peptides into clinical studies for the benefit of patients.
Highlights
The field of nuclear medicine has advocated a theragnostic approach towards personalised medicine by combining patient stratification with positron emission tomography (PET) imaging and radionuclide therapy using theragnostic pairs such as gallium-68 (68Ga, β+ emitter) and lutetium-177 (177Lu, β−emitter) [1]
A bottleneck in the routine treatment of patients using LutatheraTM is expected to result from the low throughput of [68 Ga]Ga-DOTA-TATE PET imaging for stratifying patients
We propose a pipeline that exemplifies the development of 68 Ga-radiopharmaceuticals alongside complementary fluorine-18 analogues, that can be produced in an almost limitless quantity and widespread availability (Figure 1); the decay characteristics of fluorine-18 (t1/2 = 110 min, β+ em = 97%) are ideal for same-day radiopharmaceutical manufacture, transportation and PET imaging
Summary
The field of nuclear medicine has advocated a theragnostic approach towards personalised medicine by combining patient stratification with positron emission tomography (PET) imaging and radionuclide therapy using theragnostic pairs such as gallium-68 (68Ga, β+ emitter) and lutetium-177 This approach was exemplified for neuroendocrine tumours (NETs) expressing the somatostatin receptor (SSTR) by combining PET imaging with [68Ga]Ga-DOTA-TATE (NETSPOTTM in the US) or [68Ga]Ga-DOTA-TOC (SomakitTOCTM in Europe) to select patients to receive the molecularly targeted radionuclide therapeutic, LutatheraTM ([177Lu]Lu-DOTA-TATE). Several factors result in [68 Ga]Ga-DOTA-TATE being unable to satisfy high clinical demand: 1) the relatively low radioactivity of gallium-68 (68 Ga) produced by 68 Ge/68 Ga generators (typically 1.8 GBq when new, from a generator authorized for patient use) limits the number of clinical doses produced from a single elution; 2) the half-life (t1/2 = 68 min) is incompatible with the satellite. The generator produced radioisotope is ideal for research institutions and hospital radiopharmacies as on-demand radioactive doses are straightforward to access and for some, more convenient and inexpensive than fluorine-18
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