Gallium (68Ga) gozetotide

Gallium (⁶⁸Ga) gozetotide or Gallium (⁶⁸Ga) PSMA-11, sold under the brand name Illuccix among others, is a radiopharmaceutical made of ⁶⁸Ga conjugated to a inhibitor of the enzyme prostate-specific membrane antigen (PSMA) known as Glu-Urea-Lys(Ahx)-HBED-CC. It is used for imaging prostate cancer by positron emission tomography (PET).^[12] The PSMA inhibitor specifically directs the radiolabeled imaging agent towards the prostate cancerous lesions in men.^[13]

Gallium (⁶⁸Ga) gozetotide

Clinical data
Trade names	Illuccix, Locametz
Other names	Gallium 68 PSMA-11, Gallium Ga 68 gozetotide (USAN US)
AHFS/Drugs.com	Micromedex Detailed Consumer Information
License data	US DailyMed: Gozetotide
Pregnancy category	AU: Exempt[1]
Routes of administration	Intravenous[2]
ATC code	V09IX14 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1] CA: ℞-only / Schedule C[3][4][5][6] US: ℞-only[2][7][8][9][10] EU: Rx-only[11]
Pharmacokinetic data
Excretion	Urine[2]
Identifiers
IUPAC name 2-[[5-[3-[[6-[[(5S)-5-carboxy-5-[[(1S)-1,3-dicarboxypropyl]carbamoylamino]pentyl]amino]-6-oxohexyl]amino]-3-oxopropyl]-2-oxidophenyl]methyl-[2-[[5-(2-carboxyethyl)-2-oxidophenyl]methyl-(carboxylatomethyl)amino]ethyl]amino]acetate;gallium-68(3+);hydron
CAS Number	1906894-20-9
PubChem CID	154572876
DrugBank	DB16019 DB16303
ChemSpider	52083842
UNII	ZJ0EKR6M10
KEGG	D12257
Chemical and physical data
3D model (JSmol)	Interactive image
SMILES [H+].C1=CC(=C(C=C1CCC(=O)NCCCCCC(=O)NCCCC[C@@H](C(=O)O)NC(=O)N[C@@H](CCC(=O)O)C(=O)O)CN(CCN(CC2=C(C=CC(=C2)CCC(=O)O)[O-])CC(=O)[O-])CC(=O)[O-])[O-].[68Ga+3]
InChI InChI=1S/C44H62N6O17.Ga/c51-34-13-8-28(22-30(34)24-49(26-40(59)60)20-21-50(27-41(61)62)25-31-23-29(9-14-35(31)52)11-16-38(55)56)10-15-37(54)46-18-4-1-2-7-36(53)45-19-5-3-6-32(42(63)64)47-44(67)48-33(43(65)66)12-17-39(57)58;/h8-9,13-14,22-23,32-33,51-52H,1-7,10-12,15-21,24-27H2,(H,45,53)(H,46,54)(H,55,56)(H,57,58)(H,59,60)(H,61,62)(H,63,64)(H,65,66)(H2,47,48,67);/q;+3/p-3/t32-,33-;/m0./s1/i;1-2 Key:AEBYHKKMCWUMKX-LNTZDJBBSA-K

The most common side effects with gallium (68Ga)-radiolabelled gozetotide are tiredness, nausea (feeling sick), constipation and vomiting.^[11]

Gallium (68Ga) gozetotide was approved for medical use in the United States in December 2021,^[14][15] and in the European Union in December 2022.^[11] It is the first drug approved by the US Food and Drug Administration (FDA) as a PET imaging agent.^[13]

Structure

Radiopharmaceuticals based on HBED are composed of three components: a chelator that has a HBED structure and two functions, a radiometal coordinated with the chelator, and a binding motif or pharmacophore that is conjugated to the chelator (such as a peptide or antibody). One of the most popular HBED chelators is HBED-CC. This chelator can create stable complexes with trivalent gallium at normal temperatures and it attaches to bioactive molecules through its propionic acid moieties.^[16]

Medical uses

Gallium (⁶⁸Ga) gozetotide is a radioactive diagnostic agent indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer.^[8][9][11]

Ga 68 PSMA-11 injections are used for PET imaging of prostate-specific membrane antigen (PSMA) positive lesions in males with prostate cancer. It can be given for the patients with suspected metastasis, and the candidates with initial definitive therapy.^[2]

History

In the early 2000s, researchers began exploring the use of PSMA as a target for imaging and therapy. The first PSMA-targeted radiotracer was developed using a different radioactive element, technetium-99m. This radiotracer, called 99mTc-MIP-1404, showed promise in preclinical studies but did not perform well in clinical trials.^[17]

In 2011, researchers started investigating the use of gallium-68, a different radioactive element, as a more suitable alternative for PSMA-targeted radiotracers. In 2013, the first Ga-PSMA radiotracer was developed by researchers at DKFZ in Germany, and it showed promising results in early clinical studies.^[18]

Since then, Ga-PSMA has been extensively studied in clinical trials, and it has been found to be a highly effective imaging agent for detecting prostate cancer lesions. It is now widely used in clinical practice, particularly for patients with recurrent prostate cancer and those with high-risk disease.

Initially gallium (⁶⁸Ga) chloride solution injections used for radiolabelling,^[19] in 2019 European Pharmacopoeia mentions gallium (⁶⁸Ga) DOTATOC injection for radiolabelling and PET imaging.^[20]

Ga 68 PSMA-11 was co-developed by researchers at University of California, Los Angeles and University of California, San Francisco, who conducted a phase III clinical trial.^[21] In December 2020, the drug was first approved by the US Food and Drug Administration (FDA) for PET imaging.^[13]

Mechanism of action

Gallium (⁶⁸Ga) gozetotide binds with prostate-specific membrane antigen (PSMA).^[2] This binds to cells that express PSMA, including malignant prostate cancer cells.^[2] The radioactive isotope of gallium, ⁶⁸Ga is responsible for emitting β+ radiations and X-rays.^[2] This helps in recording images by positron emission tomography (PET) and CT scan.^[2]

Society and culture

Legal status

On 13 October 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Locametz, intended for the diagnosis of prostate cancer.^[22] The applicant for this medicinal product is Novartis Europharm Limited.^[22] Locametz was approved for medical use in the European Union in December 2022.^[11][23]

Names

Gallium (⁶⁸Ga) gozetotide is the international nonproprietary name (INN).^[24]