Table 2.

Overview of in vitro and in vivo studies in α-PRRT. OS = overall survival, D₁₀ = absorbed dose to reduce survival to 10%, MPC = murine pheochromocytoma cell.

Author	Radiopharmaceutical	Aim	Findings
Chan [61]	[213Bi]Bi-DOTA-TATE	Determine whether TAT efficacy in vivo is related to tumour size in two SSTR2 +ve cell lines.	Improved OS, increased tumour doubling time vs. control in small (50 mm3) and large (200 mm3) CA20948 and H69 tumours. Several cures in small tumour cohort. No toxicity.
Chan [62]	[213Bi]Bi-DOTA-TATE	Investigate optimal radiolabelling conditions (peptide amount, quencher, pH) for [213Bi]Bi-DOTATATE.	>3.5 nmol DOTATATE required for >99% incorporation with 100 MBq 213Bi. Optimised conditions: pH = 8.3, TRIS = 0.15 mol/L in 800 µL. Ascorbic acid (0.9 mmol/L) required to avoid radiolysis.
Chan [63]	[213Bi]Bi-DOTA-TATE	Evaluate the therapeutic effect of TAT with and without renal protection using L lysine in vivo.	MTA in healthy mice = 13, 21.7 MBq with/without renal protection. In tumour-bearing, median OS > 30 d at 17 MBq, severe weight loss and mortality at 33 MBq. Renal protection improved OS.
Chan [64]	[213Bi]Bi-DOTA-TATE	Develop methods to determine relationship between absorbed dose and cell killing in vitro. Compare cytotoxicity across radiations in various cell lines.	In CA20948, D10 = 3 Gy, 18 Gy and 5 Gy for [213Bi]Bi-DOTATATE, [177Lu]Lu-DOTATATE and 137Cs. In BON, [177Lu]Lu-DOTATATE had no effect, D10 for [213Bi]Bi-DOTATATE, 137Cs = 2.5 Gy, 4.5 Gy.
Chapeau [65]	[212Pb]Pb-eSOMA-01	Develop new octreotate derivatives with non-DOTA chelators and assess their potential for TAT of NETs with Pb.	New SSTR2-targetting ligands labelled successfully with 212/203Pb, eSOMA-01 showed favourable biodistribution compared to DOTAM-TATE.
Cieslik [66]	[225Ac]Ac-L1-TATE	Assess feasibility of L1 as chelator with 177Lu, 211At, 225Ac in two SSTR2 +ve cell lines, evaluate biodistribution in MPC tumour bearing mice.	L1 can bind radionuclides for imaging and therapy. Preferable fast and mild labelling compared to DOTA. [225Ac]Ac-L1 produced with molar activity > 0.25 MBq/nmol.
Graf [67]	[225Ac]Ac-DOTA-TOC	Assess γH2AX foci formation as biomarker of cytotoxicity and response to [225Ac]Ac-DOTATOC and [177Lu]Lu-DOTATOC in vitro and in vivo.	High tumour control rate with single treatment of both agents. Number of γH2AX foci correlated with apoptosis (in vitro) and tumour growth, showing potential as biomarker.
Handula [60]	[225Ac]Ac-DOTA-JR11	Investigate potential of [225Ac]Ac-DOTA-JR11 (antagonist) for therapy of NETs via mouse model.	Low tumour-to-kidney ratio of absorbed dose is limiting for therapeutic use of [225Ac]Ac-DOTA-JR11.
King [68]	[225Ac]Ac-MACROPA-TATE	Synthesise and characterise MACROPA TATE, compare performance with DOTA TATE in labelling efficiency, stability, binding, efficacy.	[225Ac]Ac-MACROPATATE showed higher renal and liver uptake and toxicity at lower activities, DOTATATE deemed superior.
Lee [46]	[212Pb]Pb-PSC-PEG2-TOC	Improve SSTR2 targeting over DOTA-based conjugates via click-chemistry-based cyclization, improved chelator design and insertion of PEG linkers.	Development of lead-specific chelator (PSC) and insertion of PEG linkers results in improved tumour uptake, retention and quicker renal clearance, and dose-dependent therapeutic effect with acceptable toxicity.
Li [47]	[212Pb]Pb-PSC-PEG-TOC	Characterise Pb-specific chelator for radiolabelling yield, stability and in vivo biodistribution.	212Pb and 212Bi stably incorporated in PSC-PEG-TOC. Biodistribution of 212Pb/212Bi-PSC-PEG-TOC were comparable. 203/212Pb showed comparable biodistribution.
Miederer [69]	[225Ac]Ac-DOTA-TOC	Compare biodistribution, toxicity and anti-tumour effect of [225Ac]Ac-DOTATOC and [177Lu]Lu-DOTATOC.	Activities > 30 kBq of 225Ac-induced tubular necrosis, weight loss. 225Ac (20 kBq) showed improved tumour growth delay vs. 177Lu (0.45 MBq).
Müller [70]	[149Tb]Tb-DOTA-NOC	Letter to the editor to highlight the potential of 149Tb for ‘α PET’.	High quality PET image of mouse injected with 7 MBq [149Tb]Tb-DOTANOC showing high tumour uptake.
Nayak [71]	[213Bi]Bi-DOTA-TOC	Compare binding, cytotoxicity, induction of apoptosis between [213Bi/177Lu]Lu-DOTATOC in human pancreatic adenocarcinoma cells.	RBE of [213Bi]Bi-DOTATOC, [177Lu]Lu-DOTATOC relative to 137Cs = 3.4, 1.0. 213Bi induced greater release of apoptosis markers in Capan-2 cells.
Norenberg [72]	[213Bi]Bi-DOTA-TOC	Evaluate quantitative labelling methods, stability, biodistribution, safety, and efficacy in vivo.	Activity-related decrease in tumour growth rate observed (>11 MBq). Mild acute but no chronic nephrotoxicity. No haemato-toxicity.
Pretze [49]	[212Pb]Pb-PSC-PEG2-TOC	Investigate the influence of different molar activities of [203/212Pb]Pb-PSC2-TOC on cell uptake.	Uptake increased with molar activity, 15–40 MBq/nmol showed highest cell uptake.
Qin [73]	[211At]At-SAB-Oct	Develop octreotide SAB conjugate to be labelled with 211At and evaluate therapeutic efficacy against SCLC.	Anti-tumour response against SCLC model demonstrated, with acceptable toxicity profile.
Stallons [74]	[212Pb]Pb-DOTAM-TATE	Determine binding and cell kill in vitro. Assess biodistribution in vivo. Establish tolerable regimen and efficacy as mono and combination therapy.	Non-toxic at <45 µCi, toxicity overcome by fractionation into 3 cycles. 79% cure rate with 3 × 10 µCi in combination with 5FU. Benefits of ascorbic acid and nephro protection demonstrated.
Tafreshi [75]	[225Ac]Ac-DOTA-TATE	Assess toxicity, biodistribution, dosimetry and efficacy in lung neuroendocrine model (H727/H69) in vivo.	Chronic progressive nephropathy at >111 kBq. Single admin produced tumour growth delay and reduction in tumour volume vs. control.
Vaidyanathan [76]	[211At]At-GIMBO	Synthesise octreotate analogue with guanidine-containing template for 211At labelling, assess in comparison with Glu-TOCA in vitro and in vivo.	Single step process to synthesise radioiodinated and astatinated octreotide analogue with positive template reported. Affinity for SSTR2 demonstrated, but high uptake in normal tissue is limiting.
Wharton [77]	[225Ac]Ac-H4noneupaX-TATE	Develop novel bifunctional chelator capable of complexing 225Ac and 155Tb for theragnostics.	H4noneupaX was characterised, then labelling of 225Ac and 155Tb assessed. SPECT/CT imaging of 155Tb demonstrates potential as theragnostic pair isotope for 225Ac therapy.
Zhao [78]	[211At]At-SPC-TOC	Investigate possible use of 211Ac-labelled octreotide to treat NSCLC.	[211At]At-SPC-octreotide showed elevated and activity-dependent apoptosis induction compared to PBS, cold peptide and unlabelled 211At.